2-(morpholin-4-yl)-1,7-naphthyridines

ABSTRACT

to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative disease as a sole agent or in combination with other active ingredients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/501,079,filed Feb. 1, 2017, now allowed; which is the U.S. national stage ofInt'l Application No. PCT/EP2015/067804, filed Aug. 3, 2015; whichclaims priority benefit of Application Nos. EP 14179692.0, filed Aug. 4,2014, and EP 15159342.3, filed Mar. 17, 2015; the entire contents ofwhich are hereby incorporated by reference.

Concurrently with this specification, an ASCII file is being submittedelectronically via EFS-Web and forms part of the official record. SeeLegal Framework for Electronic Filing System—Web (EFS-Web), 74 FR 55200,55202 (Oct. 27, 2009). The entire content of the ASCII text fileentitled “Sequence_Listing.txt” (created on May 8, 2018 and having asize of 45.1 kb) is incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to substituted2-(morpholin-4-yl)-1,7-naphthyridine compounds, a process for theirproduction and the use thereof.

BACKGROUND OF THE INVENTION

The integrity of the genome of eukaryotic cells is secured by complexsignaling pathways, referred to as the DNA damage response (DDR), andmultiple DNA repair mechanisms. Upon recognizing DNA damage activationof the DDR pathways results in cell cycle arrest, suppression of generaltranslation, induction of DNA repair, and, finally, in cell survival orcell death. Proteins that directly recognize aberrant DNA structures,such as the MRE11-Rad50-Nbs1 complex recognizing DNA double strandbreaks by binding to double-stranded DNA ends, or RPA (replicationprotein A) binding to single stranded DNA, recruit and activate the mostupstream kinases of the DDR pathway, ATM (ataxia-telangiectasiamutated), ATR (ATM- and Rad3-related, UniProtKB/Swiss-Prot Q13535), andDNA-PKcs (DNA-dependent protein kinase). Whereas ATM is primarilyactivated by DNA double strand breaks, and DNA-PKcs is mainly involvedin non-homologous end joining process of DNA repair, ATR responds to abroad spectrum of DNA damage, including double-strand breaks and lesionsderived from interference with DNA replication. Major components ofdownstream signaling of ATM include Chk2 and p53, whereas ATR signalinginvolves Chk1 and cdc25. Knockout of the ATR gene in mice isembryonically lethal and ATR knockout cells develop chromosome breaksand undergo apoptosis [E. J. Brown, D. Baltimore: ATR disruption leadsto chromosomal fragmentation and early embryonic lethality. Genes Dev.14, 397-402, 2000]. In contrast, ATM is not essential for cell survivalalthough ATM knockout cells are hypersensitive to ionizing radiation andagents which cause DNA double-strand breaks.

ATR, which forms a complex with ATRIP (ATR-interacting protein,UniProtKB/Swiss-Prot Q8WXE1) is mainly activated by long stretches ofsingle-stranded DNA which are generated by the continuing DNA unwindingactivity of helicases upon stalled replication. This replication stresswith stalled replication forks may be induced by ultraviolet light,certain chemotherapeutic drugs, hydroxyurea, or aberrant oncogenicsignaling resulting in increased replication initiation or originfiring. Activation of ATR results in inhibition of the cell cycle in Sor G2 phase via the Chk1-cdc25 pathway and in suppression of late originfiring. The cell gains time to resolve the replication stress and,eventually, to restart replication after the source of stress has beenremoved. As the ATR pathway ensures cell survival after replicationstress it potentially contributes to resistance to chemotherapy. Thusinhibition of ATR kinase activity could be useful for cancer treatment.

In oncogene-driven tumor cells (e.g. Ras mutation/upregulation, Mycupregulation, CyclinE overexpression) increased replication stress hasbeen observed as compared to healthy normal cells. ATR suppression inRas oncogene driven cells was reported to result in substantial tumorcell killing [O. Gilad, B Y Nabet, et al.: Combining ATR suppressionwith oncogenic Ras synergistically increases genomic instability,causing synthetic lethality or tumorigenesis in a dosage-dependentmanner. Cancer Res. 70, 9693-9702, 2010].

Although ATM and ATR are principally activated by different types of DNAdamage their signaling includes some cross-talk thus that they can, atleast partially, substitute for each others function. This findingsuggests some tumor-cell selectivity of pharmaceutical inhibition ofATR. A healthy normal cell, which has ATM and ATR pathways in parallel,arrests in G1 phase of the cell cycle upon induced DNA damage even inpresence of an ATR inhibitor. In contrast, a tumor cell which most oftendeficient in ATM and/or p53 signaling relies on the ATR pathway andundergoes cell death in presence of an ATR inhibitor. This suggests thatATR inhibitors may be used for the treatment of tumors with deficientATM signaling and/or p53 function.

Details of DDR signaling and the functional role of ATM and ATR wererecently reviewed in: E. Fokas, R. Prevo et al.: Targeting ATR in DNAdamage response and cancer therapeutics. Cancer Treatment Rev 40,109-117, 2014. J. M. Wagner & S. H. Kaufmann: Prospects for the use ofATR inhibitors to treat cancer. Pharmaceuticals 3, 1311-1334, 2010. D.Woods & J. J. Tuchi: Chemotherapy induced DNA damage response. CancerBiol. Thera. 14, 379-389, 2013. A. Marechal & L. Zou: DNA damage sensingby the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5,a012716, 2013. M. K. Zeman & K. A. Cimprich: Causes and consequences ofreplication stress. Nat. Cell Biol. 16, 2-9, 2014. S. Llona-Minguez, A.Haglund et al.: Chemical strategies for development of ATR inhibitors.Exp. Rev. Mol. Med. 16, e10, 2014.

Some inhibitors of ATR kinase are known (J. Med. Chem. 2013, 56,2125-2138; Exp. Rev. Mol. Med. 16, e10, 2014; WO2010054398A1;WO2010071837A1; WO2010073034A1; WO2011143399A1; WO2011143419A1;WO2011143422A1; WO2011143423A2; WO2011143425A2; WO2011143426A1;WO2011154737A1; WO2011163527A1; WO2012138938A1; WO2012178123A1;WO2012178124A1; WO2012178125A1; WO2013049719A1; WO2013049720A1;WO2013049722A1; WO2013049859A1; WO2013071085A1; WO2013071088A1;WO2013071090A1; WO2013071093A1; WO2013071094A1; WO2013152298A1;WO2014062604A1; WO2014089379A1; WO2014143240).

WO 0058307 describe aryl fused 2,4-disubstituted pyridines as NK3receptor ligands. However, no 1,7-naphthyridine compounds areexemplified.

WO 2006039718 describe aryl nitrogen-containing bicyclic compounds forthe prophylaxis and treatment of protein kinase mediated diseases.However, no 1,7-naphthyridine compounds are exemplified.

WO 2008017461 and the Journal of Medicinal Chemistry 2011, 54(22),7899-7910 describe 1,7-naphthyridine derivatives as p38 MAP kinaseinhibitors. The 8-position of the 1,7-naphthyridine derivatives issubstituted with a phenyl ring. No 1,7-naphthyridine compounds areexemplified, which are substituted with a heteroaryl group in the8-position of the 1,7-naphthyridine.

There is a need for the development of ATR inhibitors for treatingdiseases, in particular hyperproliferative diseases. The problem to besolved by the present invention is to provide further compounds whichinhibit ATR. It was found, surprisingly, that2-(Morpholin-4-yl)-1,7-naphthyridines of general formula (I) or (Ib)inhibit ATR.

In accordance with a first aspect, the present invention coverscompounds of general formula (I)

in which:

-   R¹ represents a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule;

-   R² represents hydrogen, halogen, —NR⁷R⁸, CN, C₁-C₆-alkyl,    C₁-C₆-alkoxy, 3- to 10-membered heterocycloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to    10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)OR⁷,    —(CO)NR⁷R⁸, —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,    —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —SiR¹⁰R¹¹R¹², —(PO)(OR⁷)₂,    —(PO)(OR⁷)R¹⁰ or —(PO)(R¹⁰)₂,    -   wherein each C₁-C₆-alkyl, C₁-C₆-alkoxy, 3- to 10-membered        heterocycloalkoxy, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to        10-membered heterocycloalkyl, phenyl or heteroaryl is optionally        substituted, one or more times, independently from each other,        with halogen, OH, —NR⁷R⁸, C₁-C₆-alkyl optionally substituted one        or more times with hydroxyl or phenyl, C₁-C₆-haloalkyl,        C₁-C₆-alkoxy, C₃-C₆-cycloalkyl, 3- to 6-membered        heterocycloalkyl, phenyl, —(CO)OR⁷, —(CO)NR⁷R⁸, —NR⁷(CO)R¹⁰,        —NR⁸(CO)OR⁷, —NR(CO)NR⁷R⁸, —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸,        —NR⁷(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂,        —(PO)(OR⁷)R¹⁰, —(PO)(R¹⁰)₂ or with a heteroaryl group which is        optionally substituted, one or more times, with C₁-C₄-alkyl;    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl;-   R³, R⁴ represent, independently from each other, hydrogen or methyl;-   R⁷, R⁸ represent, independently from each other, hydrogen,    C₁-C₆-alkyl, C₃-C₆-cycloalkyl or phenyl, which phenyl is optionally    substituted, one or more times, with halogen; or-   R⁷ and R⁸ together represent a 4-, 5-, 6- or 7-membered cyclic amine    group, which is optionally substituted, one or more times,    independently from each other, with a substituent selected from    C₁-C₆-alkyl, C₁-C₆-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic    amine group optionally containing one further heteroatom selected    from the group consisting of O, N and S;-   R⁹ represents C₁-C₄-alkyl or phenyl, wherein each C₁-C₄-alkyl or    phenyl is optionally substituted, one or more times, independently    from each other, with R³;-   R¹⁰ represents C₁-C₄-alkyl; or-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a 5-    to 8-membered heterocycloalkyl group;-   R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷, —(CO)NR⁷R⁸ or CN;-   R¹² represents hydrogen or C₁-C₄-alkyl;-   R¹ represents halogen, OH, —NR⁷R⁸, CN, NO₂, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, —(CO)OR⁷ or —(CO)NR⁷R⁸;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

The terms as mentioned in the present text have the following meanings:The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as meaning a linear orbranched, saturated, monovalent hydrocarbon group having 1, 2, 3, 4, 5,or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl,iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl,1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or an isomer thereof.Particularly, said group has 1, 2, 3 or 4 carbon atoms (“C₁-C₄-alkyl”),e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl,tert-butyl group, more particularly 1, 2 or 3 carbon atoms(“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl or iso-propyl group.

The term “C₁-C₆-haloalkyl” is to be understood as meaning a linear orbranched, saturated, monovalent hydrocarbon group in which the term“C₁-C₆-alkyl” is defined supra, and in which one or more hydrogen atomsis replaced by a halogen atom, in identically or differently, i.e. onehalogen atom being independent from another. Particularly, said halogenatom is F. Said C₁-C₆-haloalkyl group is, for example, —CF₃, —CHF₂,—CH₂F, —CF₂CF₃ or —CH₂CF₃.

The term “C₁-C₄-hydroxyalkyl” is to be understood as meaning a linear orbranched, saturated, monovalent hydrocarbon group in which the term“C₁-C₄-alkyl” is defined supra, and in which one or more hydrogen atomsis replaced by a hydroxy group, e.g. a hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl,2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl,3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl,1-hydroxy-2-methyl-propyl group.

The term “C₁-C₆-alkoxy” is to be understood as meaning a linear orbranched, saturated, monovalent, hydrocarbon group of formula —O-alkyl,in which the term “alkyl” is defined supra, e.g. a methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy,pentoxy, iso-pentoxy, or n-hexoxy group, or an isomer thereof.Particularly, said “C₁-C₆-alkoxy” can contain 1, 2, 3, 4 or 5 carbonatoms, (a “C₁-C₅-alkoxy”), preferably 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkoxy”).

The term “C₁-C₆-haloalkoxy” is to be understood as meaning a linear orbranched, saturated, monovalent C₁-C₆-alkoxy group, as defined supra, inwhich one or more of the hydrogen atoms is replaced, in identically ordifferently, by a halogen atom. Particularly, said halogen atom is F.Said C₁-C₆-haloalkoxy group is, for example, —OCF₃, —OCHF₂, —OCH₂F,—OCF₂CF₃, or —OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as meaning a linear orbranched, monovalent hydrocarbon group, which contains one or moredouble bonds, and which has 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4carbon atoms (“C₂-C₄-alkenyl”), particularly 2 or 3 carbon atoms(“C₂-C₃-alkenyl”), it being understood that in the case in which saidalkenyl group contains more than one double bond, then said double bondsmay be isolated from, or conjugated with, each other. Said alkenyl groupis, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl,homoallyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl,(Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl,(E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl,hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl,(Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl,(Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl,2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl,3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl,3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl,(E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl,(Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl,(E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl,1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl,4-methylpent-4-enyl, 3-methylpent-4-enyl, 2-methylpent-4-enyl,1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl,(Z)-3-methylpent-3-enyl, (E)-2-methylpent-3-enyl,(Z)-2-methylpent-3-enyl, (E)-1-methylpent-3-enyl,(Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl,(Z)-4-methylpent-2-enyl, (E)-3-methylpent-2-enyl,(Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl,(Z)-2-methylpent-2-enyl, (E)-1-methylpent-2-enyl,(Z)-1-methylpent-2-enyl, (E)-4-methylpent-1-enyl,(Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl,(Z)-3-methylpent-1-enyl, (E)-2-methylpent-1-enyl,(Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl,(Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl,1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl,(E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl, (E)-1-ethylbut-2-enyl,(Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl,2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl,2-propylprop-2-enyl, 1-propylprop-2-enyl, 2-isopropylprop-2-enyl,1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methyihexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₃-C₁₀-cycloalkyl” is to be understood as meaning a saturated,monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5,6, 7, 8, 9 or 10 carbon atoms (“C₃-C₁₀-cycloalkyl”). SaidC₃-C₁₀-cycloalkyl group is for example, a monocyclic hydrocarbon ring,e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon ring,e.g. a perhydropentalenylene or decalin ring. Particularly, said ringcontains 3, 4, 5 or 6 carbon atoms (“C₃-C₆-cycloalkyl”), preferablycyclopropyl.

The term “3- to 10-membered heterocycloalkyl” is to be understood asmeaning a saturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl orC₁-C₆-haloalkyl group; it being possible for said heterocycloalkyl groupto be attached to the rest of the molecule via any one of the carbonatoms or, if present, the nitrogen atom.

Particularly, said 3- to 10-membered heterocycloalkyl can contain 2, 3,4, or 5 carbon atoms, and one or more of the above-mentionedheteroatom-containing groups (a “3- to 6-membered heterocycloalkyl”),more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms,and one or more of the above-mentioned heteroatom-containing groups (a“5- to 6-membered heterocycloalkyl”).

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl,piperazinyl, or trithianyl, or a 7-membered ring, such as a diazepanylring, for example. Optionally, said heterocycloalkyl can be benzo fused.Preferably, the 3- to 6-membered heterocycloalkyl is atetrahydrofuranyl, tetrahydropyranyl or piperazinyl.

Said heterocycloalkyl can be bicyclic, such as, without being limitedthereto, a 5,5-membered ring, e.g. ahexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclicring, e.g. a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring.

As mentioned supra, said nitrogen atom-containing ring can be partiallyunsaturated, i.e. it can contain one or more double bonds, such as,without being limited thereto, a 2,5-dihydro-1H-pyrrolyl,4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl ring,for example, or, it may be benzo-fused, such as, without being limitedthereto, a dihydroisoquinolinyl ring, for example.

The term “3- to 10-membered heterocycloalkoxy” of formula—O-heterocycloalkyl, in which the term “heterocycloalkyl” is definedsupra, is to be understood as meaning a saturated, monovalent, mono- orbicyclic hydrocarbon ring which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbonatoms, and one or more heteroatom-containing groups selected from C(═O),O, S, S(═O), S(═O)₂, NR^(a), in which R^(a) represents a hydrogen atom,a C₁-C₆-alkyl or C₁-C₆-haloalkyl group and which is connected to therest of the molecule via an oxygen atom, e.g. a pyrrolidineoxy,tetrahydrofuraneoxy or tetrahydropyranoxy.

The term “4- to 10-membered heterocycloalkenyl” is to be understood asmeaning an unsaturated, monovalent, mono- or bicyclic hydrocarbon ringwhich contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms, and one or moreheteroatom-containing groups selected from C(═O), O, S, S(═O), S(═O)₂,NR^(a), in which R^(a) represents a hydrogen atom, or a C₁-C₆-alkyl orC₁-C₆-haloalkyl group; it being possible for said heterocycloalkenylgroup to be attached to the rest of the molecule via any one of thecarbon atoms or, if present, the nitrogen atom. Examples of saidheterocycloalkenyl may contain one or more double bonds, e.g.4H-pyranyl, 2H-pyranyl, 3,6-dihydro-2H-pyran-4-yl,3,6-dihydro-2H-thiopyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl,3H-diazirinyl, 2,5-dihydro-1H-pyrrolyl, [1,3]dioxolyl,4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl,2,5-dihydrothiophenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl,4H-[1,4]thiazinyl or 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl group orit may be benzo fused.

The term “heteroaryl” is understood as meaning a monovalent,monocyclic-, bicyclic- or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), 5 or 6 or 9 or 10 ring atoms (a “5- to 10-membered heteroaryl”group) or particularly 5 or 6 ring atoms (“5- to 6-membered heteroaryl”group), and which contains at least one heteroatom which may beidentical or different, said heteroatom being such as oxygen, nitrogenor sulfur, and in addition in each case can be benzocondensed.Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc., and benzoderivatives thereof, such as, for example, benzofuranyl, benzothienyl,benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl,indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, forexample, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl,indolizinyl, purinyl, etc., and benzo derivatives thereof; orcinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, xanthenyl, oxepinyl or 1H-pyrrolo[2,3-b]pyridin-4-yl, etc.

In general, and unless otherwise mentioned, the heteroarylic orheteroarylenic radicals include all the possible isomeric forms thereof,e.g. the positional isomers thereof. Thus, for some illustrativenon-restricting example, the term pyridinyl or pyridinylene includespyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene,pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienyleneincludes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃, C₁- C₄,C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of “C₁-C₆-haloalkyl”or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkenyl” and“C₂-C₆-alkynyl”, is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₁-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄. C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

Further, as used herein, the term “C₂-C₄”, as used throughout this text,e.g. in the context of “C₂-C₄-alkenyl” is to be understood as meaning aalkenyl group having a finite number of carbon atoms of 2 to 4, i.e. 2,3 or 4 carbon atoms. It is to be understood further that said term“C₂-C₄” is to be interpreted as any sub-range comprised therein, e.g.C₂-C₄, C₂-C₃, C₃-C₄.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence may be preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention may contain one or more asymmetriccentre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric centre, and diastereomeric mixtures in the case ofmultiple asymmetric centres. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

The compounds of the present invention may contain sulphur atoms whichare asymmetric, such as an asymmetric sulphoxide or sulphoximine group,of structure:

for example,in which * indicates atoms to which the rest of the molecule can bebound.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention may be achieved by any suitable state of the art method, suchas chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Those skilled in the art will furtherrecognise that acid addition salts of the claimed compounds may beprepared by reaction of the compounds with the appropriate inorganic ororganic acid via any of a number of known methods. Alternatively, alkaliand alkaline earth metal salts of acidic compounds of the invention areprepared by reacting the compounds of the invention with the appropriatebase via a variety of known methods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorphs, or as a mixture of more than one polymorphs, inany ratio.

When radicals in the compounds of the present invention are substituted,the radicals may be mono- or polysubstituted, unless specifiedotherwise. In the context of the present invention, all radicals whichoccur more than once are defined independently of one another.Substitution by one, two or three identical or different substituents ispreferred.

In the context of the present invention, the term “treatment” or“treating” includes inhibition, retardation, checking, alleviating,attenuating, restricting, reducing, suppressing, repelling or healing ofa disease (the term “disease” includes but is not limited a condition, adisorder, an injury or a health problem), or the development, the courseor the progression of such states and/or the symptoms of such states.The term “therapy” is understood here to be synonymous with the term“treatment”.

The terms “prevention”, “prophylaxis” or “preclusion” are usedsynonymously in the context of the present invention and refer to theavoidance or reduction of the risk of contracting, experiencing,suffering from or having a disease or a development or advancement ofsuch states and/or the symptoms of such states.

The treatment or prevention of a disease may be partial or complete.

In another embodiment, the present invention covers compounds of generalformula (I)

in which:

-   R¹ represents a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule;

-   R² represents hydrogen, halogen, —NR⁷R⁸, CN, C₁-C₆-alkyl,    C₁-C₆-alkoxy, 3- to 10-membered heterocycloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to    10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)OR⁷,    —(CO)NR⁷R⁸, —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,    —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —SiR¹⁰R¹¹R¹², —(PO)(OR⁷)₂,    —(PO)(OR⁷)R¹⁰ or —(PO)(R¹⁰)₂,    -   wherein each C₁-C₆-alkyl, C₁-C₆-alkoxy, 3- to 10-membered        heterocycloalkoxy, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to        10-membered heterocycloalkyl, phenyl or heteroaryl is optionally        substituted, one or more times, independently from each other,        with halogen, OH, —NR⁷R⁸, C₁-C₆-alkyl, 3- to 6-membered        heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl,        —(CO)OR⁷, —(CO)NR⁷R⁸, —NR⁷(CO)R¹⁰, —NR⁸(CO)OR⁷, —NR⁸(CO)NR⁷R⁸,        —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,        —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰,        —(PO)(R¹⁰)₂ or with a heteroaryl group which is optionally        substituted, one or more times, with C₁-C₄-alkyl;    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl;-   R³, R⁴ represent, independently from each other, hydrogen or methyl;-   R⁷, R⁸ represent, independently from each other, hydrogen or    C₁-C₆-alkyl; or-   R⁷ and R⁸ together represent a 4-, 5-, 6- or 7-membered cyclic amine    group, which is optionally substituted, one or more times,    independently from each other, with a substituent selected from    C₁-C₆-alkyl, C₁-C₆-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic    amine group optionally containing one further heteroatom selected    from the group consisting of O, N and S;-   R⁹ represents C₁-C₄-alkyl or phenyl, wherein each C₁-C₄-alkyl or    phenyl is optionally substituted, one or more times, independently    from each other, with R³;-   R¹⁰ represents C₁-C₄-alkyl; or-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a 5-    to 8-membered heterocycloalkyl group;-   R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷, —(CO)NR⁷R⁸ or CN;-   R¹² represents hydrogen or C₁-C₄-alkyl;-   R¹ represents halogen, OH, —NR⁷R⁸, CN, NO₂, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, —(CO)OR⁷ or —(CO)NR⁷R⁸;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (I), supra, in which:

-   R¹ represents a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule;

-   R² represents hydrogen, fluoro, chloro, CN, C₁-C₄-alkyl,    C₁-C₄-alkoxy, 3- to 6-membered heterocycloalkoxy, C₂-C₄-alkenyl,    C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to    6-membered heterocycloalkenyl, phenyl, 5- to 6-membered heteroaryl,    —(CO)NR⁷R⁸, —(SO₂)R⁹, —SR⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰,    -   wherein each C₁-C₄-alkyl, C₁-C₄-alkoxy, 3- to 6-membered        heterocycloalkoxy, C₂-C₄-alkenyl, C₃-C₆-cycloalkyl, 3- to        6-membered heterocycloalkyl, phenyl, 5- to 6-membered        heteroaryl, is optionally substituted, one or more times,        independently from each other, with fluoro, chloro, OH, —NR⁷R⁸,        C₁-C₄-alkyl, 5-membered heterocycloalkyl, phenyl, —NR⁸(CO)OR⁷,        —(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂ or with a 5- to        6-membered heteroaryl group which is optionally substituted, one        or more times, with C₁-C₄-alkyl;    -   wherein each 4- to 6-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl;-   R³, R⁴ represent, independently from each other, hydrogen or methyl;-   R⁷, R⁸ represent, independently from each other, hydrogen or    C₁-C₄-alkyl;-   R⁹ represents C₁-C₄-alkyl;-   R¹⁰ represents C₁-C₄-alkyl; or-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a    6-membered heterocycloalkyl group;-   R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib)

in which R¹, R², R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are as definedfor the compound of general formula (I) supra or infra.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents hydrogen, fluoro, chloro, CN, methyl, C₁-C₄-alkoxy,    C₂-C₃-alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, 4- to    6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl,    —(SO₂)R⁹, —SR⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰,    -   wherein each methyl, C₁-C₄-alkoxy, C₂-C₃-alkenyl, cyclopropyl,        3- to 6-membered heterocycloalkyl, phenyl, pyridinyl or        thiazolyl is optionally substituted, one or more times,        independently from each other, with fluoro, chloro, OH, —NR⁷R⁸,        methyl, 5-membered heterocycloalkyl, —NR⁸(CO)OR⁷, —(SO₂)R⁹,        —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂, or with a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   wherein each 4- to 6-membered heterocycloalkenyl is optionally        substituted, one or more times, with methyl;

-   R⁴ represents hydrogen or methyl;

-   R⁷, R⁸ represent, independently from each other, hydrogen or    C₁-C₄-alkyl;

-   R⁹ represents C₁-C₄-alkyl;

-   R¹⁰ represents C₁-C₄-alkyl; or

-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a    6-membered heterocycloalkyl group;

-   R¹¹ represents hydrogen, methyl, —(CO)OR⁷;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents hydrogen, fluoro, chloro, CN, methyl, cyclopropyl,    C₂-C₃-alkenyl, C₁-C₄-alkoxy, 3- to 10-membered heterocycloalkyl, 4-    to 10-membered heterocycloalkenyl, 5- to 10-membered heteroaryl,    phenyl, —NR⁷R⁸, —N═(SO)R⁹R¹⁰, —((SO)═NR¹¹)R¹⁰, —(SO₂)R⁹, —SR⁹,    -   wherein each methyl, C₂-C₃-alkenyl, C₁-C₄-alkoxy, 3- to        10-membered heterocycloalkyl, 5- to 10-membered heteroaryl,        phenyl is optionally substituted, one or more times,        independently from each other, with fluoro, chloro, OH, —NR⁷R⁸,        C₁-C₄-alkyl, cyclopropyl, C₁-C₆-haloalkyl, C₁-C₄-alkoxy,        C₁-C₄-hydroxyalkyl, benzyl, 5- to 6-membered heterocycloalkyl,        —NR⁸(CO)OR⁷, —(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂ or with a        group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, with methyl;

-   R⁷, R⁸ represent, independently from each other, hydrogen,    C₁-C₆-alkyl, cyclopropyl or optionally halogenated phenyl;

-   R⁹ represents C₁-C₄-alkyl;

-   R¹⁰ represents C₁-C₄-alkyl; or

-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a    6-membered heterocycloalkyl group;

-   R¹¹ represents hydrogen, methyl, —(CO)OR⁷;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents CN, C₁-C₄-alkoxy, —(SO₂)R⁹, —SR⁹, cyclopropyl, —NR⁷R⁸,    —N═(SO)R⁹R¹⁰, phenyl, 5- to 10-membered heteroaryl, 3- to    10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkenyl,    -   wherein each C₁-C₄-alkoxy, phenyl, 5- to 10-membered heteroaryl,        3- to 10-membered heterocycloalkyl is optionally substituted,        one or more times, independently from each other, with fluoro,        chloro, —NR⁷R⁸, C₁-C₄-alkyl, cyclopropyl, C₁-C₆-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-hydroxyalkyl, benzyl, 5- to 6-membered        heterocycloalkyl, —NR⁸(CO)OR⁷, —(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰;

-   R⁷, R⁸ represent, independently from each other, hydrogen,    C₁-C₆-alkyl, cyclopropyl or optionally halogenated phenyl;

-   R⁹ represents C₁-C₄-alkyl;

-   R¹⁰ represents C₁-C₄-alkyl; or

-   R⁹ and R¹⁰ together, in case of —N═(SO)R⁹R¹⁰ group, represent a    6-membered heterocycloalkyl group;

-   R¹¹ represents hydrogen;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents CN, methoxy, ethoxy, propoxy, butyloxy, isopropoxy,    methylsulfanyl, cyclopropyl, —NR⁷R⁸,    (4-oxido-1,4λ⁴-oxathian-4-ylidene)amino, phenyl, pyridinyl,    thiazolyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrrolyl, thienyl, pyrazolyl,    1,2-oxazolyl, imidazolyl, tetrahydro-2H-pyranyl,    3,6-dihydro-2H-thiopyranyl, piperidinyl, piperazinyl,    5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, methanesulphonyl,    -   wherein each ethoxy, propoxy, butyloxy, phenyl, pyridinyl,        thiazolyl, pyrroly, thienyl, pyrazolyl, 1,2-oxazolyl,        imidazolyl, piperidinyl or piperazinyl is optionally        substituted, one or more times, independently from each other,        with fluoro, chloro, —NR⁷R⁸, methyl, ethyl, 2,2,-dimethylethyl,        cyclopropyl, trifluoromethyl, methoxy, hydroxymethyl, benzyl,        piperazinyl, —NR⁸(CO)OR⁷, methanesulphonyl, —((SO)═NR¹¹)R¹⁰;

-   R⁷, R⁸ represent, independently from each other, hydrogen, methyl,    2,2-dimethylethyl, 2,2-dimethylpropyl, cyclopropyl or fluorophenyl;

-   R¹⁰ represents methyl;

-   R¹¹ represents hydrogen;    or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents hydrogen, halogen, —NR⁷R⁸, CN, C₁-C₆-alkyl,    C₁-C₆-alkoxy, 3- to 10-membered heterocycloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to    10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)OR⁷,    —(CO)NR⁷R⁸, —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,    —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —SiR¹⁰R¹¹R¹², —(PO)(OR⁷)₂,    —(PO)(OR⁷)R¹⁰ or —(PO)(R¹⁰)₂,    -   wherein each C₁-C₆-alkyl, C₁-C₆-alkoxy, 3- to 10-membered        heterocycloalkoxy, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to        10-membered heterocycloalkyl, phenyl or heteroaryl is optionally        substituted, one or more times, independently from each other,        with halogen, OH, —NR⁷R⁸, C₁-C₆-alkyl optionally substituted        with hydroxyl or phenyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,        C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl,        —(CO)OR⁷, —(CO)NR⁷R⁸, —NR⁷(CO)R¹⁰, NR⁸(CO)OR⁷, —NR⁸(CO) NR⁷R⁸,        —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,        —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰,        —(PO)(R¹⁰)₂ or with a heteroaryl group which is optionally        substituted, one or more times, with C₁-C₄-alkyl;    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl;

-   R³, R⁴ represent, independently from each other, hydrogen or methyl;

-   R⁷, R⁸ represent, independently from each other, hydrogen,    C₁-C₆-alkyl, C₃-C₆-cycloalkyl or phenyl, which phenyl is optionally    substituted, one or more times, with halogen; or

-   R⁷ and R⁸ together represent a 4-, 5-, 6- or 7-membered cyclic amine    group, which is optionally substituted, one or more times,    independently from each other, with a substituent selected from    C₁-C₆-alkyl, C₁-C₆-haloalkyl, said 4-, 5-, 6- or 7-membered cyclic    amine group optionally containing one further heteroatom selected    from the group consisting of O, N and S;

-   R⁹ represents C₁-C₄-alkyl or phenyl, wherein each C₁-C₄-alkyl or    phenyl is optionally substituted, one or more times, independently    from each other, with R³;

-   R¹⁰ represents C₁-C₄-alkyl; or R⁹ and R¹ together, in case of    —N═(SO)R⁹R¹⁰ group, represent a 5- to 8-membered heterocycloalkyl    group;

-   R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷, —(CO)NR⁷R⁸ or CN;

-   R¹² represents hydrogen or C₁-C₄-alkyl;

-   R¹³ represents halogen, OH, —NR⁷R⁸, CN, NO₂, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy, C₂-C₆-alkenyl,    C₃-C₆-cycloalkyl, —(CO)OR⁷ or —(CO)NR⁷R⁸.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents hydrogen, halogen, —NR⁷R⁸, CN, C₁-C₆-alkyl,    C₁-C₄-alkoxy, 3- to 10-membered heterocycloalkoxy, C₂-C₄-alkenyl,    C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to    10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)NR⁷R⁸,    —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰,    —(PO)(R¹⁰)₂,    -   wherein each C₁-C₆-alkyl, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl, 3- to        10-membered heterocycloalkyl, phenyl or heteroaryl is optionally        substituted, one or more times, independently from each other,        with        -   halogen, OH, amino, —NR⁷R⁸,        -   C₁-C₄-alkyl optionally substituted with hydroxyl or phenyl,        -   C₁-C₂-haloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyl, 3- to            6-membered heterocycloalkyl, phenyl, —(CO)OR⁷, —(CO)NR⁷R⁸,            —NR⁷(CO)R¹⁰, —NR⁸(CO)OR⁷, —(SO₂)R⁹, —SR⁹, —NR⁷(SO₂)R⁹,            —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰, or with a            heteroaryl group;    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with methyl;

-   R⁴ represents hydrogen or methyl;

-   R⁷, R⁸ represent, independently from each other, hydrogen,    C₁-C₆-alkyl, C₃-C₆-cycloalkyl or phenyl, which phenyl is optionally    substituted, one or more times, with halogen;

-   R⁹ represents C₁-C₄-alkyl or phenyl, wherein each C₁-C₄-alkyl or    phenyl is optionally substituted, one or more times, independently    from each other, with R³;

-   R¹⁰ represents C₁-C₄-alkyl; or

-   R⁹ and R¹ together, in case of —N═(SO)R⁹R¹⁰ group, represent a 5- to    8-membered heterocycloalkyl group;

-   R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷, —(CO)NR⁷R⁸ or CN;

-   R¹³ represents halogen, OH or C₁-C₆-alkoxy.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   R¹ represents:

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule;

-   R² represents hydrogen, chloro,-amino, propylamino, dimethylamino,    methyl(propyl)amino, methyl(2-methylpropyl)amino,    2,2-dimethylpropyl(methyl)amino, cyclopropyl(methyl)amino,    methyl(phenyl)amino, CN, methyl, ethyl, propan-2-yl,    3-methylbutan-2-yl, pentan-3-yl, hexan-2-yl, 3,3-dimethylbutan-2-yl,    methoxy, ethoxy, propoxy, butoxy, 2-methyl-propan-1-yloxy,    propan-2-yloxy, (2-oxotetrahydrofuran-3-yl)oxy, propenyl,    cyclopropyl, cyclohexyl, azetidinyl,-pyrrolidinyl,    2-oxo-1,3-oxazolidin-2-one, tetrahydro-2H-pyranyl,    tetrahydro-2H-thiopyran-4-yl, piperidinyl, piperazinyl, morpholinyl,    azepanyl, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl,    3-oxo-piperazin-1-yl, 2-oxo-1,3-oxazinan-3-yl,    1-oxidotetrahydro-2H-thiopyran-4-yl,    1,1-dioxidotetrahydro-2H-thiopyran-4-yl,    1,1-dioxido-1,2-thiazolidin-2-yl,    5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,    3-oxa-8-azabicyclo[3.2.1]oct-8-yl,    1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl,    (3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl,    (1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl,    1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-yl,    2,5-dihydro-1H-pyrrol-1-yl, 3,6-dihydro-2H-pyran-4-yl,    1,2,5,6-tetrahydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl,    3,6-dihydro-2H-thiopyran-4-yl, phenyl, 1,3-dihydro-2H-isoindol-2-yl,    3,4-dihydroquinolin-1(2H)-yl, 3,4-dihydroisoquinolin-2(1H)-yl,    pyrrolyl, pyrazolyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl,    triazolyl, oxadiazolyl, pyridinyl, pyrimidinyl,    2-oxo-1,2-dihydropyridin-4-yl, indolyl, benzothiophenyl, quinolinyl,    isoquinolinyl, 1H-pyrrolo[2,3-b]pyridin-4-yl,    6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, —(CO)NH₂,    methylsulfonyl, ethylsulfonyl, propan-2-ylsulfonyl, phenylsulfonyl,    methylsulfinyl, ethylsulfinyl, propan-2-ylsulfinyl, phenylsulfinyl,    methylsulfanyl, ethylsulfanyl, propan-2-ylsulfanyl, phenylsulfanyl,    —N═(SO)dimethyl, —N═(SO)diethyl,

-   -   wherein * indicates the point of attachment of said group with        the rest of the molecule, —(PO)(O-methyl)₂,        —(PO)(O-ethyl)methyl, —(PO)(O-2-methylpropyl)methyl,        —(PO)(O-ethyl)₂-methylpropyl, —(PO)dimethyl, —(PO)diethyl,        -   wherein each methyl, ethyl, propan-2-yl, 3-methylbutan-2-yl,            pentan-3-yl, hexan-2-yl, 3,3-dimethylbutan-2-yl, methoxy,            ethoxy, propoxy, 2-methyl-propan-1-yloxy, butoxy,            cyclopropyl, cyclohexyl, azetidinyl, pyrrolidinyl,            piperidinyl, piperazinyl, morpholinyl, 3-oxo-piperazin-1-yl,            phenyl, pyrrolyl, pyrazolyl, thiophenyl, imidazolyl,            oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl,            pyrimidinyl, indolyl,

-   -   -   is optionally substituted, one or more times, independently            from each other, with fluoro, chloro, bromo, OH, amino,            —NH-cyclopropyl, dimethylamino, methyl, ethyl, propan-1-yl,            propan-2-yl, 2-methylpropyl, tert-butyl, hydroxymethyl,            2-hydroxyethyl, 2-methyl-2-hydroxypropan-1-yl,            2-hydroxypropan-2-yl, benzyl, fluoroethyl, difluoromethyl,            trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl,            cyclopropyl, cyclobutyl, tetrahydrofuranyl,            tetrahydropyranyl, phenyl, —(CO)O-methyl, (CO)O-tert-butyl,            —(CO)NH₂, —(CO)NH-methyl, —(CO)NH-tert-butyl,            —(CO)dimethylamino, —(CO)piperidin-1-yl,            —(CO)NH-cyclopropyl, —NH(CO)methyl, —NH(CO)O-tert-butyl,            methylsulfonyl, ethylsulfonyl, propan-2-ylsulfonyl,            phenylsulfonyl, methylsulfanyl, —(SO₂)NR⁷R⁸, NH(SO₂)methyl,            —((SO)═NH)methyl, —((SO)═NH)ethyl, —((SO)═NH)propan-2-yl,            —((SO)═N-methyl)methyl, —((SO)═N—(CO)O-ethyl)methyl,            —((SO)═N—(CN))methyl, —((SO)═N—(CO)NH-ethyl)methyl,            —(PO)(O-methyl)₂, —(PO)(OH)(O-methyl) or with furanyl or            pyrazolyl,        -   wherein each 1,2,5,6-tetrahydropyridin-3-yl,            1,2,3,6-tetrahydropyridin-4-yl is optionally substituted,            one or more times, independently from each other, with            methyl;

-   R₄ represents hydrogen or methyl.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents 2,2-dimethylpropyl(methyl)amino,        cyclopropyl(methyl)amino, methyl(phenyl)amino,        3-methylbutan-2-yl, cyclopropyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyran-4-yl, piperidinyl, piperazinyl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,        3,6-dihydro-2H-thiopyran-4-yl, phenyl, pyrrolyl, pyrazolyl,        thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,        1H-pyrrolo[2,3-b]pyridin-4-yl or        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each 3-methylbutan-2-yl, cyclopropyl, piperidinyl,            piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl,            imidazolyl, oxazolyl, thiazolyl or pyridinyl is optionally            substituted, one or two or three times, independently from            each other, with            -   fluoro, chloro, OH, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, hydroxymethyl, benzyl,                fluoroethyl, trifluoromethyl, methoxy, cyclopropyl,                —(CO)O-methyl, methylsulfonyl, methylsulfanyl or                —((SO)═NH)methyl;

    -   R⁴ represents methyl.

In accordance with another embodiment the present invention coverscompounds of general formula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents tetrahydro-2H-thiopyran-4-yl, piperidinyl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, phenyl, pyrrolyl,        pyrazolyl, oxazolyl, pyridinyl or        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each piperidinyl, phenyl, pyrrolyl, pyrazolyl,            oxazolyl or pyridinyl is optionally substituted, one or two            times, independently from each other, with fluoro, amino,            methyl, ethyl, propan-2-yl, hydroxymethyl, methoxy,            cyclopropyl, methylsulfonyl, methylsulfanyl or            —((SO)═NH)methyl;

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents 2,2-dimethylpropyl(methyl)amino,        cyclopropyl(methyl)amino, methyl(phenyl)amino,        3-methylbutan-2-yl, cyclopropyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyran-4-yl, piperidin-4-yl, piperazin-1-yl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,        3,6-dihydro-2H-thiopyran-4-yl, phenyl, pyrrol-2-yl,        1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiophen-2-yl, thiophen-3-yl,        1H-imidazol-5-yl, 1,2-oxazol-5-yl, 1,3-thiazol-5-yl,        pyridine-3-yl, pyridine-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl or        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each 3-methylbutan-2-yl, cyclopropyl,            piperidin-4-yl, piperazin-1-yl, phenyl, pyrrol-2-yl,            1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiophen-2-yl,            thiophen-3-yl, 1H-imidazol-5-yl, 1,2-oxazol-5-yl,            1,3-thiazol-5-yl, pyridine-3-yl or pyridine-4-yl is            optionally substituted, one or two or three times,            independently from each other, with            -   fluoro, chloro, OH, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, hydoxymethyl, benzyl,                2-fluoroethyl, trifluoromethyl, methoxy, cyclopropyl,                —(CO)O-methyl, methylsulfonyl, methylsulfanyl or                —((SO)═NH)methyl;

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents tetrahydro-2H-thiopyran-4-yl, piperidin-4-yl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, phenyl, pyrrol-2-yl,        1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1,2-oxazol-5-yl,        1,3-thiazol-5-yl, pyridine-3-yl,        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each piperidin-4-yl, phenyl, pyrrol-2-yl,            1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1,2-oxazol-5-yl,            pyridine-3-yl is optionally substituted, one or two times,            independently from each other, with            -   fluoro, OH, amino, methyl, ethyl, propan-2-yl,                hydoxymethyl, 2-fluoroethyl, methoxy, cyclopropyl,                ethylsulfonyl, methylsulfanyl, —((SO)═NH)methyl,

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents phenyl, pyrazolyl, thiophenyl or pyridinyl,        -   wherein each phenyl, pyrazolyl, thiophenyl or pyridinyl is            optionally substituted, one or two times, independently from            each other, with            -   fluoro, chloro, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, benzyl, fluoroethyl,                trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl,                methylsulfanyl, —((SO)═NH)methyl,

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,        thiophen-2-yl, thiophen-3-yl or pyridine-3-yl, pyridine-4-yl,        -   wherein each phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,            thiophen-2-yl, thiophen-3-yl, pyridine-3-yl or            pyridine-4-yl, is optionally substituted, one or two times,            independently from each other, with            -   fluoro, chloro, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, benzyl, fluoroethyl,                trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl,                methylsulfanyl, —((SO)═NH)methyl,

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (Ib), in which

-   -   R¹ represents:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   R² represents phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl or        pyridine-3-yl,        -   wherein each phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl or            pyridine-3-yl, is optionally substituted, one or two times,            independently from each other, with            -   fluoro, amino, methyl, ethyl, propan-1-yl, propan-2-yl,                tert-butyl, benzyl, fluoroethyl, trifluoromethyl,                methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl,                —((SO)═NH)methyl,

    -   R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹ represents a group selected from

wherein * indicates the point of attachment of said group with the restof the molecule.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹ represents a group selected from

wherein * indicates the point of attachment of said group with the restof the molecule.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹ represents

wherein * indicates the point of attachment of said group with the restof the molecule.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R² represents hydrogen, fluoro, chloro,CN, C₁-C₄-alkyl, C₁-C₄-alkoxy, 3- to 6-membered heterocycloalkoxy,C₂-C₄-alkenyl, C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, 4-to 6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl,—(CO)NR⁷R⁸, —(SO₂)R⁹, —SR⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰,

-   -   wherein each C₁-C₄-alkyl, C₁-C₄-alkoxy, 3- to 6-membered        heterocycloalkoxy, C₂-C₄-alkenyl, C₃-C₆-cycloalkyl, 3- to        6-membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is        optionally substituted, one or more times, independently from        each other, with        -   fluoro, chloro, OH, —NR⁷R⁸, C₁-C₄-alkyl, 5-membered            heterocycloalkyl, phenyl, —NR⁸(CO)OR⁷, —(SO₂)R⁹,            —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂ or a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   wherein each 4- to 6-membered heterocycloalkenyl is optionally        substituted, one or more times, with C₁-C₄-alkyl.

In another embodiment, the present invention relates to compounds offormula (I) or (Ib), in which R² represents hydrogen, fluoro, chloro,CN, C₁-C₄-alkyl, C₁-C₄-alkoxy, 3- to 6-membered heterocycloalkoxy,C₂-C₃-alkenyl, C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, 4-to 6-membered heterocycloalkenyl, phenyl, pyridinyl, thiazolyl,—(CO)NR⁷R⁸, —(SO₂)R⁹, —SR⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰,

-   -   wherein each C₁-C₄-alkyl, C₁-C₄-alkoxy, 3- to 6-membered        heterocycloalkoxy, C₂-C₄-alkenyl, C₃-C₆-cycloalkyl, 3- to        6-membered heterocycloalkyl, phenyl, pyridinyl or thiazolyl is        optionally substituted, one or more times, independently from        each other, with fluoro, chloro, OH, —NR⁷R⁸, C₁-C₄-alkyl,        5-membered heterocycloalkyl, phenyl, —NR(CO)OR⁷, —(SO₂)R⁹,        —((SO)═NR¹¹)R¹⁰, —(PO)(OR⁷)₂ or a group selected from:

-   -   -   wherein * indicates the point of attachment of said group            with the rest of the molecule;

    -   wherein each 4- to 6-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl.

In another embodiment the present invention relates to compounds ofgeneral formula (I) or (Ib), in which R² represents hydrogen, halogen,—NR⁷R⁸, CN, C₁-C₆-alkyl, C₁-C₆-alkoxy, 3- to 10-memberedheterocycloalkoxy, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to 10-memberedheterocycloalkyl, 4- to 10-membered heterocycloalkenyl, phenyl,heteroaryl, —(CO)OR⁷, —(CO)NR⁷R⁸, —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸,—NR⁷(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —SiR¹⁰R¹¹R¹², —(PO)(OR⁷)₂,—(PO)(OR⁷)R¹⁰ or —(PO)(R¹⁰)₂,

-   -   wherein each C₁-C₆-alkyl, C₁-C₆-alkoxy, 3- to 10-membered        heterocycloalkoxy, C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to        10-membered heterocycloalkyl, phenyl or heteroaryl is optionally        substituted, one or more times, independently from each other,        with halogen, OH, —NR⁷R⁸, C₁-C₆-alkyl optionally substituted        with hydroxy or phenyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy,        C₃-C₆-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl,        —(CO)OR⁷, —(CO)NR⁷R⁸, —NR⁷(CO)R¹⁰, —NR⁸(CO)OR⁷, —NR⁸(CO) NR⁷R⁸,        —(SO₂)R⁹, —(SO)R⁹, —SR⁹, —(SO₂)NR⁷R⁸, —NR⁷(SO₂)R⁹,        —((SO)═NR¹¹)R¹⁰, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰,        —(PO)(R¹⁰)₂ or with a heteroaryl group which is optionally        substituted, one or more times, with C₁-C₄-alkyl;    -   wherein each 4- to 10-membered heterocycloalkenyl is optionally        substituted, one or more times, independently from each other,        with C₁-C₄-alkyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R² represents CN, methoxy, ethoxy,propoxy, butyloxy, isopropoxy, methylsulfanyl, cyclopropyl, —NR⁷R⁸,(4-oxido-1,4λ⁴-oxathian-4-ylidene)amino, phenyl, pyridinyl, thiazolyl,1H-pyrrolo[2,3-b]pyridin-4-yl, pyrrolyl, thienyl, pyrazolyl,1,2-oxazolyl, imidazolyl, tetrahydro-2H-pyranyl,3,6-dihydro-2H-thiopyranyl, piperidinyl, piperazinyl,5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, methanesulphonyl,—((SO)═NR¹¹)R¹⁰,

-   -   wherein each ethoxy, propoxy, butyloxy, phenyl, pyridinyl,        thiazolyl, pyrroly, thienyl, pyrazolyl, 1,2-oxazolyl,        imidazolyl, piperidinyl or piperazinyl is optionally        substituted, one or more times, independently from each other,        with fluoro, chloro, —NR⁷R⁸, methyl, ethyl, 2,2,-dimethylethyl,        cyclopropyl, trifluoromethyl, methoxy, hydroxymethyl, benzyl,        piperazinyl, —NR⁸(CO)OR⁷, methanesulphonyl,        S-methylsulfonimidoyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R² represents hydrogen, chloro,-amino,propylamino, dimethylamino, methyl(propyl)amino,methyl(2-methylpropyl)amino, 2,2-dimethylpropyl(methyl)amino,cyclopropyl(methyl)amino, methyl(phenyl)amino, CN, methyl, ethyl,propan-2-yl, 3-methylbutan-2-yl, pentan-3-yl, hexan-2-yl,3,3-dimethylbutan-2-yl, methoxy, ethoxy, propoxy, butoxy,2-methyl-propan-1-yloxy, propan-2-yloxy, (2-oxotetrahydrofuran-3-yl)oxy,propenyl, cyclopropyl, cyclohexyl, azetidinyl,-pyrrolidinyl,2-oxo-1,3-oxazolidin-2-one, tetrahydro-2H-pyranyl,tetrahydro-2H-thiopyran-4-yl, piperidinyl, piperazinyl, morpholinyl,azepanyl, 2-oxo-pyrrolidin-1-yl, 2-oxo-piperidin-1-yl,3-oxo-piperazin-1-yl, 2-oxo-1,3-oxazinan-3-yl,1-oxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxidotetrahydro-2H-thiopyran-4-yl,1,1-dioxido-1,2-thiazolidin-2-yl,5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,3-oxa-8-azabicyclo[3.2.1]oct-8-yl,1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl,(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl,(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl,1,1-dioxido-1-thia-6-azaspiro[3.3]hept-6-yl 2,5-dihydro-1H-pyrrol-1-yl,3,6-dihydro-2H-pyran-4-yl, 1,2,5,6-tetrahydropyridin-3-yl,1,2,3,6-tetrahydropyridin-4-yl, 3,6-dihydro-2H-thiopyran-4-yl, phenyl,1,3-dihydro-2H-isoindol-2-yl, 3,4-dihydroquinolin-1(2H)-yl,3,4-dihydroisoquinolin-2(1H)-yl, pyrrolyl, pyrazolyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyridinyl,pyrimidinyl, 2-oxo-1,2-dihydropyridin-4-yl, indolyl, benzothiophenyl,quinolinyl, isoquinolinyl, 1H-pyrrolo[2,3-b]pyridin-4-yl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl, —(CO)NH₂, methylsulfonyl,ethylsulfonyl, propan-2-ylsulfonyl, phenylsulfonyl, methylsulfinyl,ethylsulfinyl, propan-2-ylsulfinyl, phenylsulfinyl, methylsulfanyl,ethylsulfanyl, propan-2-ylsulfanyl, phenylsulfanyl, —N═(SO)dimethyl,—N═(SO)diethyl,

wherein * indicates the point of attachment of said group with the restof the molecule, —(PO)(O-methyl)₂, —(PO)(O-ethyl)methyl,—(PO)(O-2-methylpropyl)methyl, —(PO)(O-ethyl)₂-methylpropyl,—(PO)dimethyl, —(PO)diethyl,

-   -   wherein each methyl, ethyl, propan-2-yl, 3-methylbutan-2-yl,        pentan-3-yl, hexan-2-yl, 3,3-dimethylbutan-2-yl, methoxy,        ethoxy, propoxy, 2-methyl-propan-1-yloxy, butoxy, cyclopropyl,        cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,        morpholinyl, 3-oxo-piperazin-1-yl, phenyl, pyrrolyl, pyrazolyl,        thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl,        oxadiazolyl, pyridinyl, pyrimidinyl, indolyl,

-   -   is optionally substituted, one or more times, independently from        each other, with fluoro, chloro, bromo, OH, amino,        —NH-cyclopropyl, dimethylamino, methyl, ethyl, propan-1-yl,        propan-2-yl, 2-methylpropyl, tert-butyl, hydroxymethyl,        2-hydroxyethyl, 2-methyl-2-hydroxypropan-1-yl,        2-hydroxypropan-2-yl, benzyl, fluoroethyl, difluoromethyl,        trifluoromethyl, methoxy, ethoxy, isopropoxy, methoxymethyl,        cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl,        phenyl, —(CO)O-methyl, (CO)O-tert-butyl, —(CO)NH₂,        —(CO)NH-methyl, —(CO)NH-tert-butyl, —(CO)dimethylamino,        —(CO)piperidin-1-yl, —(CO)NH-cyclopropyl, —NH(CO)methyl,        —NH(CO)O-tert-butyl, methylsulfonyl, ethylsulfonyl,        propan-2-ylsulfonyl, phenylsulfonyl, methylsulfanyl,        —(SO₂)NR⁷R⁸, NH(SO₂)methyl, —((SO)═NH)methyl, —((SO)═NH)ethyl,        —((SO)═NH)propan-2-yl, —((SO)═N-methyl)methyl,        —((SO)═N—(CO)O-ethyl)methyl, —((SO)═N—(CN))methyl,        —((SO)═N—(CO)NH-ethyl)methyl, —(PO)(O-methyl)₂,        —(PO)(OH)(O-methyl) or with furanyl, pyrazolyl,    -   wherein each 1,2,5,6-tetrahydropyridin-3-yl,        1,2,3,6-tetrahydropyridin-4-yl is optionally substituted, one or        more times, independently from each other, with methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents 2,2-dimethylpropyl(methyl)amino,        cyclopropyl(methyl)amino, methyl(phenyl)amino,        3-methylbutan-2-yl, cyclopropyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyran-4-yl, piperidinyl, piperazinyl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,        3,6-dihydro-2H-thiopyran-4-yl, phenyl, pyrrolyl, pyrazolyl,        thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,        1H-pyrrolo[2,3-b]pyridin-4-yl,        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each 3-methylbutan-2-yl, cyclopropyl, piperidinyl,            piperazinyl, phenyl, pyrrolyl, pyrazolyl, thiophenyl,            imidazolyl, oxazolyl, thiazolyl, pyridinyl, is optionally            substituted, one or two or three times, independently from            each other, with            -   fluoro, chloro, OH, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, hydroxymethyl, benzyl,                fluoroethyl, trifluoromethyl, methoxy, cyclopropyl,                —(CO)O-methyl, methylsulfonyl, methylsulfanyl,                —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents tetrahydro-2H-thiopyran-4-yl, piperidinyl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, phenyl, pyrrolyl,        pyrazolyl, oxazolyl, pyridinyl,        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each piperidinyl, phenyl, pyrrolyl, pyrazolyl,            oxazolyl, pyridinyl, is optionally substituted, one or two            times, independently from each other, with            -   fluoro, amino, methyl, ethyl, propan-2-yl,                hydroxymethyl, methoxy, cyclopropyl, methylsulfonyl,                methylsulfanyl, —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents 2,2-dimethylpropyl(methyl)amino,        cyclopropyl(methyl)amino, methyl(phenyl)amino,        3-methylbutan-2-yl, cyclopropyl, tetrahydro-2H-pyranyl,        tetrahydro-2H-thiopyran-4-yl, piperidin-4-yl, piperazin-1-yl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl,        3,6-dihydro-2H-thiopyran-4-yl, phenyl, pyrrol-2-yl,        1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiophen-2-yl, thiophen-3-yl,        1H-imidazol-5-yl, 1,2-oxazol-5-yl, 1,3-thiazol-5-yl,        pyridine-3-yl, pyridine-4-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl or        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each 3-methylbutan-2-yl, cyclopropyl,            piperidin-4-yl, piperazin-1-yl, phenyl, pyrrol-2-yl,            1H-pyrazol-5-yl, 1H-pyrazol-4-yl, thiophen-2-yl,            thiophen-3-yl, 1H-imidazol-5-yl, 1,2-oxazol-5-yl,            1,3-thiazol-5-yl, pyridine-3-yl or pyridine-4-yl is            optionally substituted, one or two or three times,            independently from each other, with            -   fluoro, chloro, OH, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, hydoxymethyl, benzyl,                2-fluoroethyl, trifluoromethyl, methoxy, cyclopropyl,                —(CO)O-methyl, methylsulfonyl, methylsulfanyl or                —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents tetrahydro-2H-thiopyran-4-yl, piperidin-4-yl,        5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl, phenyl, pyrrol-2-yl,        1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1,2-oxazol-5-yl,        1,3-thiazol-5-yl, pyridine-3-yl or        6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl,        -   wherein each piperidin-4-yl, phenyl, pyrrol-2-yl,            1H-pyrazol-5-yl, 1H-pyrazol-4-yl, 1,2-oxazol-5-yl or            pyridine-3-yl is optionally substituted, one or two times,            independently from each other, with            -   fluoro, OH, amino, methyl, ethyl, propan-2-yl,                hydoxymethyl, 2-fluoroethyl, methoxy, cyclopropyl,                ethylsulfonyl, methylsulfanyl or —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds ofgeneral formula (I) or (Ib), in which R² represents 5- to 6-memberedheteroaryl, which is optionally substituted, one or two times,independently from each other, with fluoro, chloro, methyl, ethyl,2,2,-dimethylethyl, cyclopropyl, trifluoromethyl, methoxy, benzyl ormethanesulphonyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents phenyl, pyrazolyl, thiophenyl or pyridinyl,        -   wherein each phenyl, pyrazolyl, thiophenyl or pyridinyl is            optionally substituted, one or two times, independently from            each other, with            -   fluoro, chloro, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, benzyl, fluoroethyl,                trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl,                methylsulfanyl or —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,        thiophen-2-yl, thiophen-3-yl, pyridine-3-yl or pyridine-4-yl,        -   wherein each phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl,            thiophen-2-yl, thiophen-3-yl, pyridine-3-yl or pyridine-4-yl            is optionally substituted, one or two times, independently            from each other, with            -   fluoro, chloro, amino, methyl, ethyl, propan-1-yl,                propan-2-yl, tert-butyl, benzyl, fluoroethyl,                trifluoromethyl, methoxy, cyclopropyl, methylsulfonyl,                methylsulfanyl or —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which

-   -   R² represents phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl or        pyridine-3-yl,        -   wherein each phenyl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl or            pyridine-3-yl is optionally substituted, one or two times,            independently from each other, with            -   fluoro, amino, methyl, ethyl, propan-1-yl, propan-2-yl,                tert-butyl, benzyl, fluoroethyl, trifluoromethyl,                methoxy, cyclopropyl, methylsulfonyl, methylsulfanyl or                —((SO)═NH)methyl.

In another embodiment the present invention relates to compounds ofgeneral formula (I) or (Ib), in which R² represents 5-memberedheteroaryl, which is optionally substituted, one or two times,independently from each other, with chloro, methyl, ethyl,2,2,-dimethylethyl, cyclopropyl, trifluoromethyl, benzyl,methanesulphonyl.

In another embodiment the present invention relates to compounds ofgeneral formula (I) or (Ib), in which R² represents pyridinyl,thiazolyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, wherein eachpyridinyl, thiazolyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl isoptionally substituted, one or two times, independently from each other,with fluoro, chloro, methyl, ethyl, 2,2,-dimethylethyl, cyclopropyl,trifluoromethyl, methoxy, benzyl, methanesulphonyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R² represents a group

wherein * indicates the point of attachment of said group with the restof the molecule;wherein R^(2a) represents C₁-C₄-alkyl and R^(2b) represents C₁-C₄-alkyl,C₃-C₆-cycloalkyl or a 5- to 6-membered heterocycloalkyl group, whereineach C₁-C₄-alkyl is optionally substituted, independently from eachother, one or more times, with fluoro, orR^(2a) and R^(2b) represent together a C₃-C₆-cycloalkyl group or a 5- to6-membered heterocycloalkyl group.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R² represents a group

wherein * indicates the point of attachment of said group with the restof the molecule;wherein R^(2a) represents methyl and R^(2b) represents C₁-C₄-alkyl,C₃-C₆-cycloalkyl or a 5- to 6-membered heterocycloalkyl group orR^(2a) and R^(2b) represent together a C₃-C₆-cycloalkyl group or a 5- to6-membered heterocycloalkyl group.

In another embodiment the present invention relates to compounds offormula (I), in which R³ represents methyl and R⁴ represents H.

In another embodiment the present invention relates to compounds offormula (I), in which R³ represents H and R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (I), in which R³ represents H and R⁴ represents H.

In another embodiment the present invention relates to compounds offormula (I), in which R³ represents methyl and R⁴ represents methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁴ represents H or methyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁴ represents H.

In a preferred embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁴ represents methyl.

In another preferred embodiment the present invention relates tocompounds of formula (I) or (Ib), in which R⁴ represents methyl in theabsolute configuration R.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁷ represents hydrogen and R⁸ representshydrogen.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁷ represents hydrogen and R⁸ representsC₁-C₄-alkyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁷ represents C₁-C₄-alkyl and R⁸represents C₁-C₄-alkyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R⁹ represents methyl, ethyl, propyl orphenyl optionally substituted with R¹³.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹⁰ represents methyl, ethyl or propyl.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹¹ represents hydrogen, methyl, ethyl or—(CO)OR⁷.

In another embodiment the present invention relates to compounds offormula (I) or (Ib), in which R¹² represents hydrogen, methyl, ethyl orpropyl.

In a further embodiment the invention relates to compounds of formula(I) or (Ib), according to any of the above-mentioned embodiments, in theform of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,or a salt thereof, or a mixture of same.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I) or (Ib), supra.

More particularly still, the present invention covers the titlecompounds of general formula (I) or (Ib), which are disclosed in theExample section of this text, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described below in the schemes 1 to 6 and/or theExperimental Section.

In particular, the present invention covers a method to preparecompounds of general formula 5,

characterized in that compounds of general formula 4, in which R³ and R⁴have the same meaning as defined for the compounds of general formula(I) or (Ib) are reacted in an organic solvent at a temperature between−20° C. and the boiling point of the solvent, preferably between −5° C.and 30° C., using a strong base to obtain compounds of general formula(5).

The preparation of compounds of general formula 5 can be performed in anaprotic organic solvent, preferably in tetrahydrofuran orN,N-dimethylformamide.

Preferred strong bases which can be used for the preparation ofcompounds of general formula 5 are UHMDS, KHMDS, NaHMDS or LDA.

In particular, the present invention covers a method to preparecompounds of general formula 8,

characterized in that compounds of general formula 7, in which R¹, R³and R⁴ have the same meaning as defined for the compounds of generalformula (I) or (Ib) are reacted in an organic solvent at a temperaturebetween −20° C. and the boiling point of the solvent, preferably between−5° C. and 30° C., using a strong base to obtain compounds of generalformula (8).

The preparation of compounds of general formula 8 can be performed in anaprotic organic solvent, preferably in tetrahydrofuran orN,N-dimethylformamide.

Preferred strong bases which can be used for the preparation ofcompounds of general formula 8 are UHMDS, KHMDS, NaHMDS or LDA.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 5,

in which R³ and R⁴ are as defined for the compound of general formula(I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 8,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 9,

in which R³ and R⁴ are as defined for the compound of general formula(I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 11,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 12,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib), supra, and X is chloro, bromo or iodo.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 15,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of general formula 16,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (Ib), particularly in themethods described herein. In particular, the present invention coverscompounds of general formula 39,

in which Y represents OH, —O—SO₂—CF₃, Cl, Br, I, SH or —SO₂Cl,preferably OH, —O—SO₂—CF₃ or Cl.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of formula

(also referred to as4,4,5,5-tetramethyl-(3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolan).

In accordance with a further aspect, the present invention coversintermediate compounds which are useful in the preparation of compoundsof the present invention of general formula (I) or (Ib), particularly inthe methods described herein. In particular, the present inventioncovers compounds of formula

(also referred to as4,4,5,5-tetramethyl-(4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane).

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 5,

in which R³ and R⁴ are as defined for the compound of general formula(I) or (Ib) supra, for the preparation of a compound of general formula(I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 8,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra, for the preparation of a compound of generalformula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 9,

in which R³ and R⁴ are as defined for the compound of general formula(I) or (Ib) supra, for the preparation of a compound of general formula(I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 11,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra, for the preparation of a compound of generalformula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 12,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib), supra, and X is chloro, bromo or iodo, for thepreparation of a compound of general formula (I) or (Ib) as definedsupra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 15,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra, for the preparation of a compound of generalformula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 16,

in which R¹, R³ and R⁴ are as defined for the compound of generalformula (I) or (Ib) supra, for the preparation of a compound of generalformula (I) or (Ib) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula 39,

in which Y represents OH, —O—SO₂—CF₃, Cl, Br, I, SH or —SO₂Cl,preferably OH, —O—SO₂—CF₃ or Cl for the preparation of a compound ofgeneral formula (I) or (Ib) as defined supra.

The compounds of general formula (I) or (Ib) according to the inventionshow a valuable spectrum of action which could not have been predicted.They are therefore suitable for use as medicaments for the treatmentand/or prophylaxis of diseases in humans and animals.

In particular, said compounds of the present invention have surprisinglybeen found to effectively inhibit ATR kinase and may therefore be usedfor the treatment or prophylaxis of diseases mediated by ATR kinase, inparticular hyperproliferative diseases.

The present invention relates to a method for using the compounds and/orpharmaceutical compositions of the present invention, to treat diseases,in particular hyperproliferative diseases. Compounds can be utilized toinhibit, block, reduce, decrease, etc., cell proliferation and/or celldivision, and/or produce apoptosis. This method comprises administeringto a mammal in need thereof, in particular a human, an amount of acompound of this invention which is effective to treat the disease.Hyperproliferative diseases include but are not limited, e.g.,psoriasis, keloids, and other hyperplasias affecting the skin, benignprostate hyperplasia (BPH), solid tumours, such as cancers of thebreast, respiratory tract, brain, reproductive organs, digestive tract,urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid andtheir distant metastases. Those diseases also include lymphomas,sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These diseases have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering compounds or pharmaceutical compositions of the presentinvention.

The present invention relates to the treatment of hyperproliferativediseases with deficient ATM signaling and/or p53 function, in particularof lung carcinoma, in particular small-cell lung cancer, colorectalcancer, bladder cancer, lymphomas, gliomas, and ovarian cancer.

In particular, the present invention relates to the treatment of lungcarcinoma, in particular small-cell lung cancer, colorectal cancer,bladder cancer, lymphomas, in particular diffuse large B-cell lymphoma(DLBC) and mantle cell lymphoma (MCL), prostate cancer, in particularcastration-resistant prostate cancer, gliomas, and ovarian cancer

The present invention further provides for the use of the compounds ofgeneral formula (I) or (Ib) and/or of the pharmaceutical compositions ofthe present invention for the production of a medicament for thetreatment and/or prophylaxis of diseases, especially of theaforementioned diseases, in particular of a hyperproliferative disease.

A further subject matter of the present invention is the use of thecompounds of general formula (I) or (Ib) and/or of the pharmaceuticalcompositions of the present invention in the manufacture of a medicamentfor the treatment and/or prophylaxis of disorders, in particular thedisorders mentioned above.

The present invention furthermore relates to the compounds of generalformula (I) or (Ib) for use in a method for the treatment and/orprophylaxis of a disease, in particular of a hyper-proliferativedisease.

The present invention further provides a method for treatment and/orprophylaxis of diseases, especially the aforementioned diseases, inparticular of a hyperproliferative disease, using an effective amount ofthe compounds of general formula (I) or (Ib) and/or of thepharmaceutical compositions of the present invention.

The present invention further provides the compounds of general formula(I) or (Ib) and/or of the pharmaceutical compositions of the presentinvention for use in the treatment and/or prophylaxis of diseases,especially of the aforementioned diseases, in particular of ahyperproliferative disease. The present invention further provides thecompounds of general formula (I) or (Ib) and/or of the pharmaceuticalcompositions of the present invention for use in a method for treatmentand/or prophylaxis of the aforementioned diseases, in particular of ahyperproliferative disease.

The present invention further provides a pharmaceutical compositioncomprising the compound of general formula (I) or (Ib), or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, with one or more excipient(s), in particularpharmaceutically suitable excipients, which are inert and nontoxic.Conventional procedures for preparing such pharmaceutical compositionsin appropriate dosage forms can be utilized.

The present invention furthermore relates to pharmaceuticalcompositions, in particular medicaments, which comprise at least onecompound according to the invention, conventionally together with one ormore pharmaceutically suitable excipient, and to their use for the abovementioned purposes.

Pharmaceutically acceptable excipients are non-toxic, preferably theyare non-toxic and inert. Pharmaceutically acceptable excipients include,inter alia,

-   -   fillers and excipients (for example cellulose, microcrystalline        cellulose, such as, for example, Avicel®, lactose, mannitol,        starch, calcium phosphate such as, for example, Di-Cafos®),    -   ointment bases (for example petroleum jelly, paraffins,        triglycerides, waxes, wool wax, wool wax alcohols, lanolin,        hydrophilic ointment, polyethylene glycols),    -   bases for suppositories (for example polyethylene glycols, cacao        butter, hard fat)    -   solvents (for example water, ethanol, Isopropanol, glycerol,        propylene glycol, medium chain-length triglycerides fatty oils,        liquid polyethylene glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetters (for example        sodium dodecyle sulphate, lecithin, phospholipids, fatty        alcohols such as, for example, Lanette®, sorbitan fatty acid        esters such as, for example, Span®, polyoxyethylene sorbitan        fatty acid esters such as, for example, Tween®, polyoxyethylene        fatty acid glycerides such as, for example, Cremophor®,        polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol        ethers, glycerol fatty acid esters, poloxamers such as, for        example, Pluronic®),    -   buffers and also acids and bases (for example phosphates,        carbonates, citric acid, acetic acid, hydrochloric acid, sodium        hydroxide solution, ammonium carbonate, trometamol,        triethanolamine)    -   isotonicity agents (for example glucose, sodium chloride),    -   adsorbents (for example highly-disperse silicas)    -   viscosity-increasing agents, gel formers, thickeners and/or        binders (for example polyvinylpyrrolidon, methylcellulose,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        carboxymethylcellulose-sodium, starch, carbomers, polyacrylic        acids such as, for example, Carbopol®, alginates, gelatine),    -   disintegrants (for example modified starch,        carboxymethylcellulose-sodium, sodium starch glycolate such as,        for example, Explotab®, cross-linked polyvinylpyrrolidon,        croscarmellose-sodium such as, for example, AcDiSol®),    -   flow regulators, lubricants, glidant and mould release agents        (for example magnesium stearate, stearic acid, talc,        highly-disperse silicas such as, for example, Aerosil®),    -   coating materials (for example sugar, shellac) and film formers        for films or diffusion membranes which dissolve rapidly or in a        modified manner (for example polyvinylpyrrolidones such as, for        example, Kollidon®, polyvinyl alcohol,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        ethylcellulose, hydroxypropylmethylcellulose phthalate,        cellulose acetate, cellulose acetate phthalate, polyacrylates,        polymethacrylates such as, for example, Eudragit®),    -   capsule materials (for example gelatine,        hydroxypropylmethylcellulose),    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates such as, for example,        Eudragit®, polyvinylpyrrolidones such as, for example,        Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene        oxides, polyethylene glycols and their copolymers and        blockcopolymers),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetine, triacetyl citrate, dibutyl        phthalate),    -   penetration enhancers,    -   stabilisers (for example antioxidants such as, for example,        ascorbic acid, ascorbyl palmitate, sodium ascorbate,        butylhydroxyanisole, butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, thiomersal,        benzalkonium chloride, chlorhexidine acetate, sodium benzoate),    -   colourants (for example inorganic pigments such as, for example,        iron oxides, titanium dioxide),    -   flavourings, sweeteners, flavour- and/or odour-masking agents.

Further excipients and procedures are described in the followingreferences, each of which is incorporated herein by reference: Powell,M. F. et al., “Compendium of Excipients for Parenteral Formulations” PDAJournal of Pharmaceutical Science & Technology 1998, 52(5), 238-311;Strickley, R. G “Parenteral Formulations of Small Molecule TherapeuticsMarketed in the United States (1999)-Part-1” PDA Journal ofPharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S.et al., “Excipients and Their Use in Injectable Products” PDA Journal ofPharmaceutical Science & Technology 1997, 51(4), 166-171.

The present invention furthermore relates to a pharmaceuticalcombination, in particular a medicament, comprising at least onecompound according to the invention and at least one or more furtheractive ingredients, in particular for the treatment and/or prophylaxisof the above mentioned diseases.

The present invention further provides a pharmaceutical combinationcomprising: one or more active ingredients selected from a compound ofgeneral formula (I) or (Ib), and one or more active ingredients selectedfrom antihyperproliferative, cytostatic or cytotoxic substances fortreatment of cancers.

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein, forexample, a first active ingredient and a second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein a firstactive ingredient and a second active ingredient are present inadmixture for simultaneous administration, such as in a formulation.Another example of a “fixed combination” is a pharmaceutical combinationwherein a first active ingredient and a second active ingredient arepresent in one unit without being in admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein a first active ingredient and a second activeingredient are present in more than one unit. One example of a non-fixedcombination or kit-of-parts is a combination wherein the first activeingredient and the second active ingredient are present separately. Thecomponents of the non-fixed combination or kit-of-parts may beadministered separately, sequentially, simultaneously, concurrently orchronologically staggered.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutically active ingredients where the combination causes nounacceptable adverse effects. The present invention relates also to suchpharmaceutical combinations. For example, the compounds of thisinvention can be combined with known chemotherapeutic agents and/oranti-cancer agents, e.g. anti-hyper-proliferative or other indicationagents, and the like, as well as with admixtures and combinationsthereof. Other indication agents include, but are not limited to,anti-angiogenic agents, mitotic inhibitors, alkylating agents,anti-metabolites, DNA-intercalating antibiotics, growth factorinhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomeraseinhibitors, biological response modifiers, or anti-hormones.

For example, the compounds of the present invention can be combined withknown antihyperproliferative, cytostatic or cytotoxic substances fortreatment of cancers.

Examples of suitable antihyperproliferative, cytostatic or cytotoxiccombination active ingredients include: 131I-chTNT, abarelix,abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib,aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin,altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione,angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin,arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab,belotecan, bendamustine, belinostat, bevacizumab, bexarotene,bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib,brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calciumfolinate, calcium levofolinate, capecitabine, capromab, carboplatin,carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin,ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine,cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid,clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib,dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox,denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride,dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine,doxorubicin, doxorubicin+estrone, dronabinol, eculizumab, edrecolomab,elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide,epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta,eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine,etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim,fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide,folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant,gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide,gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron,granulocyte colony stimulating factor, histamine dihydrochloride,histrelin, hydroxycarbamide, I-125 seeds, lansoprazole, ibandronic acid,ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib,imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate,interferon alfa, interferon beta, interferon gamma, iobitridol,iobenguane (123I), iomeprol, ipilimumab, irinotecan, Itraconazole,ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide,lenograstim, lentinan, letrozole, leuprorelin, levamisole,levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol,melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate,methoxsalen, methylaminolevulinate, methylprednisolone,methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin,mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphinehydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin,naloxone+pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine,neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide,nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab,octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole,ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone,oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin,palladium-103 seed, palonosetron, pamidronic acid, panitumumab,pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta(methoxyPEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane,perfosfamide, Pertuzumab, picibanil, pilocarpine, pirarubicin,pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate,polyvinylpyrrolidone+sodium hyaluronate, polysaccharide-K, pomalidomide,ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone,procarbazine, procodazole, propranolol, quinagolide, rabeprazole,racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed,ramosetron, ramucirumab, ranimustine, rasburicase, razoxane,refametinib, regorafenib, risedronic acid, rhenium-186 etidronate,rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium(153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T,sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol,streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomabmerpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur,tegafur+gimeracil+oteracil, temoporfin, temozolomide, temsirolimus,teniposide, testosterone, tetrofosmin, thalidomide, thiotepa,thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumabemtansine, treosulfan, tretinoin, trifluridine+tipiracil, trilostane,triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan,ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib,vinblastine, vincristine, vindesine, vinflunine, vinorelbine,vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres,zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

In a preferred embodiment the pharmaceutical combination of the presentinvention comprises

a compound of general formula (I) or (Ib), andone or more active ingredients selected from carboplatin and cisplatin.

Generally, the use of antihyperproliferative, cytostatic or cytotoxiccombination active ingredients in combination with a compound orpharmaceutical composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,(5) provide for a higher response rate among treated patients,(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,(7) provide a longer time for tumor progression, and/or(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

In addition, the compounds of general formula (I) can also be used incombination with radiotherapy and/or surgical intervention.

In a further embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In another embodiment of the present invention, a cell is killed bytreating the cell with at least one DNA damaging agent. That is, aftertreating a cell with one or more compounds of the invention to sensitizethe cell to cell death, the cell is treated with at least one DNAdamaging agent to kill the cell. DNA damaging agents useful in thepresent invention include, but are not limited to, chemotherapeuticagents (e.g., cisplatinum), ionizing radiation (X-rays, ultravioletradiation), carcinogenic agents, and mutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

The compounds of general formula (I) or (Ib) can act systemically and/orlocally. For this purpose, they can be administered in a suitablemanner, for example by the oral, parenteral, pulmonal, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,otic route, or as an implant or stent.

The compounds of general formula (I) or (Ib) can be administered inadministration forms suitable for these administration routes.

Suitable administration forms for oral administration are those whichrelease the compounds of general formula (I) or (Ib) in a rapid and/ormodified manner, work according to the prior art and contain thecompounds of general formula (I) or (Ib) in crystalline and/or amorphousand/or dissolved form, for example tablets (uncoated or coated tablets,for example with enteric or retarded-dissolution or insoluble coatingswhich control the release of the compound of general formula (I) or(Ib)), tablets or films/wafers which disintegrate rapidly in the oralcavity, films/lyophilizates, capsules (for example hard or soft gelatincapsules), sugar-coated tablets, granules, pellets, powders, emulsions,suspensions, aerosols or solutions.

Parenteral administration can be accomplished with avoidance of anabsorption step (for example by an intravenous, intraarterial,intracardial, intraspinal or intralumbal route) or with inclusion of anabsorption (for example by an intramuscular, subcutaneous,intracutaneous, percutaneous or intraperitoneal route). Suitableadministration forms for parenteral administration include injection andinfusion formulations in the form of solutions, suspensions, emulsions,lyophilizates or sterile powders.

For the other administration routes, suitable examples arepharmaceutical forms for inhalation or inhalation medicaments (includingpowder inhalers, nebulizers), nasal drops, solutions or sprays; tablets,films/wafers or capsules for lingual, sublingual or buccaladministration, films/wafers or capsules, suppositories, ear or eyepreparations (for example eye baths, ocular insert, ear drops, earpowders, ear-rinses, ear tampons), vaginal capsules, aqueous suspensions(lotions, shaking mixtures), lipophilic suspensions, ointments, creams,transdermal therapeutic systems (for example patches), milk, pastes,foams, dusting powders, implants, intrauterine coils, vaginal rings orstents.

The compounds of general formula (I) or (Ib) can be converted to theadministration forms mentioned. This can be done in a manner known perse, by mixing with pharmaceutically suitable excipients.

These excipients include carriers (for example microcrystallinecellulose, lactose, mannitol), solvents (e.g. liquid polyethyleneglycols), emulsifiers and dispersing or wetting agents (for examplesodium dodecylsulphate, polyoxysorbitan oleate), binders (for examplepolyvinylpyrrolidone), synthetic and natural polymers (for examplealbumin), stabilizers (e.g. antioxidants, for example ascorbic acid),dyes (e.g. inorganic pigments, for example iron oxides) and flavourand/or odour correctants.

Pharmaceutically acceptable excipients are non-toxic, preferably theyare non-toxic and inert. Pharmaceutically acceptable excipients include,inter alia: fillers and excipients (for example cellulose,microcrystalline cellulose, such as, for example, Avicel®, lactose,mannitol, starch, calcium phosphate such as, for example, Di-Cafos®),

-   -   ointment bases (for example petroleum jelly, paraffins,        triglycerides, waxes, wool wax, wool wax alcohols, lanolin,        hydrophilic ointment, polyethylene glycols),    -   bases for suppositories (for example polyethylene glycols, cacao        butter, hard fat)    -   solvents (for example water, ethanol, Isopropanol, glycerol,        propylene glycol, medium chain-length triglycerides fatty oils,        liquid polyethylene glycols, paraffins),    -   surfactants, emulsifiers, dispersants or wetters (for example        sodium dodecyle sulphate, lecithin, phospholipids, fatty        alcohols such as, for example, Lanette®, sorbitan fatty acid        esters such as, for example, Span®, polyoxyethylene sorbitan        fatty acid esters such as, for example, Tween®, polyoxyethylene        fatty acid glycerides such as, for example, Cremophor®,        polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol        ethers, glycerol fatty acid esters, poloxamers such as, for        example, Pluronic®),    -   buffers and also acids and bases (for example phosphates,        carbonates, citric acid, acetic acid, hydrochloric acid, sodium        hydroxide solution, ammonium carbonate, trometamol,        triethanolamine)    -   isotonicity agents (for example glucose, sodium chloride),    -   adsorbents (for example highly-disperse silicas)    -   viscosity-increasing agents, gel formers, thickeners and/or        binders (for example polyvinylpyrrolidon, methylcellulose,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        carboxymethylcellulose-sodium, starch, carbomers, polyacrylic        acids such as, for example, Carbopol®, alginates, gelatine),    -   disintegrants (for example modified starch,        carboxymethylcellulose-sodium, sodium starch glycolate such as,        for example, Explotab®, cross-linked polyvinylpyrrolidon,        croscarmellose-sodium such as, for example, AcDiSol®),    -   flow regulators, lubricants, glidant and mould release agents        (for example magnesium stearate, stearic acid, talc,        highly-disperse silicas such as, for example, Aerosil®),    -   coating materials (for example sugar, shellac) and film formers        for films or diffusion membranes which dissolve rapidly or in a        modified manner (for example polyvinylpyrrolidones such as, for        example, Kollidon®, polyvinyl alcohol,        hydroxypropylmethylcellulose, hydroxypropylcellulose,        ethylcellulose, hydroxypropylmethylcellulose phthalate,        cellulose acetate, cellulose acetate phthalate, polyacrylates,        polymethacrylates such as, for example, Eudragit®),    -   capsule materials (for example gelatine,        hydroxypropylmethylcellulose),    -   synthetic polymers (for example polylactides, polyglycolides,        polyacrylates, polymethacrylates such as, for example,        Eudragit®, polyvinylpyrrolidones such as, for example,        Kollidon®, polyvinyl alcohols, polyvinyl acetates, polyethylene        oxides, polyethylene glycols and their copolymers and        blockcopolymers),    -   plasticizers (for example polyethylene glycols, propylene        glycol, glycerol, triacetine, triacetyl citrate, dibutyl        phthalate),    -   penetration enhancers,    -   stabilisers (for example antioxidants such as, for example,        ascorbic acid, ascorbyl palmitate, sodium ascorbate,        butylhydroxyanisole, butylhydroxytoluene, propyl gallate),    -   preservatives (for example parabens, sorbic acid, thiomersal,        benzalkonium chloride, chlorhexidine acetate, sodium benzoate),    -   colourants (for example inorganic pigments such as, for example,        iron oxides, titanium dioxide),    -   flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention further provides medicaments which comprise atleast one compound of general formula (I) or (Ib), typically togetherwith one or more inert, nontoxic, pharmaceutically suitable excipients,and the use thereof for the aforementioned purposes.

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyperproliferative diseases by standardtoxicity tests and by standard pharmacological assays for thedetermination of treatment of the conditions identified above inmammals, and by comparison of these results with the results of knownactive ingredients or medicaments that are used to treat theseconditions, the effective dosage of the compounds of this invention canreadily be determined for treatment of each desired indication. Theamount of the active ingredient to be administered in the treatment ofone of these conditions can vary widely according to such considerationsas the particular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

In spite of this, it may be necessary to deviate from the amountsspecified, specifically depending on body weight, administration route,individual behaviour towards the active ingredient, type of formulation,and time or interval of administration. For instance, less than theaforementioned minimum amount may be sufficient in some cases, while theupper limit mentioned has to be exceeded in other cases. In the case ofadministration of greater amounts, it may be advisable to divide theminto several individual doses over the day.

The percentages in the tests and examples which follow are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for liquid/liquidsolutions are based in each case on volume.

Syntheses of Compounds (Overview):

The compounds of the present invention can be prepared as described inthe following section. The schemes and the procedures described belowillustrate general synthetic routes to the compounds of general formula(I) of the invention and are not intended to be limiting. It is clear tothe person skilled in the art that the order of transformations asexemplified in the schemes can be modified in various ways. The order oftransformations exemplified in the schemes is therefore not intended tobe limiting. In addition, interconversion of any of the substituents canbe achieved before and/or after the exemplified transformations. Thesemodifications can be such as the introduction of protecting groups,cleavage of protecting groups, exchange, reduction or oxidation offunctional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example P.G.M. Wuts and T.W. Greene in “Protective Groupsin Organic Synthesis”, 4^(th) edition, Wiley 2006). Specific examplesare described in the subsequent paragraphs. Further, it is possible thattwo or more successive steps may be performed without work-up beingperformed between said steps, e.g. a “one-pot” reaction, as iswell-known to the person skilled in the art.

The syntheses of the 2-(morpholin-4-yl)-1,7-naphthyridine derivativesaccording to the present invention are preferably carried out accordingto the general synthetic sequence, shown in schemes 1-6.

The starting material methyl 3-amino-2-chloropyridine-4-carboxylate 3(CAS No: 173435-41-1) is commercially available or can be preparedaccording to a literature procedure (see Journal of HeterocyclicChemistry, 38(1), 99-104; 2001).

Step 1→2 (Scheme 1) Amide Formation

In the first step (scheme 1), morpholine derivative 1 (which iscommercially available or described in the literature) can be convertedto the corresponding acetamide 2 using an acetylating agent. Thestarting morpholine could either be used as a salt (e.g. HCl salt) or asthe free amine.

For example the morpholine 1 can be acetylated using acetyl chloride inan organic solvent such as dichloromethane in the presence of a basesuch as K₂CO₃. The acetylation can also be performed using aceticanhydride in pyridine. Alternatively, acetic acid, a base and anactivating reagent generating an active ester in situ in an organicsolvent can be used for the transformation. For a review see: C. A. G.N. Montalbetti and V. Falque Tetrahedron 2005, 61, 10827-10852 andreferences therein).

Step 3→4 (Scheme 1) Amidine Formation

Methyl 3-amino-2-chloropyridine-4-carboxylate 3 is reacted withmorpholine amide of formula 2 in an amidine forming reaction to givecompounds of the general formula 4. Typically the reaction is performedwith POCl₃ neat or in an organic solvent at a temperature range between0° C. and the boiling point of the selected solvent. Preferably ahalogenated solvent such as chloroform, DCE or DCM is used for thereaction.

Step 4→5 (Scheme 1) Naphthyridine Formation

The amidines of formula 4 can be converted to the corresponding2-(morpholin-4-yl)-1,7-naphthyridines of formula 5. Typically thereaction is performed in an organic solvent at a temperature between−20° C. and the boiling point of the selected solvent using a strongbase. Preferably UHMDS, KHMDS, NaHMDS or LDA are used as base.

Step 5→8 (Scheme 1)

Palladium Catalyzed Reaction with Boronic Acids

The chloronaphthyridines of formula 5 can be reacted with a boronic acidderivative R¹—B(OR)₂ to give a compound of formula 8. The boronic acidderivative may be a boronic acid (R=—H) or an ester of the boronic acid,e.g. its isopropyl ester (R=—CH(CH₃)₂), preferably an ester derived frompinacol in which the boronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R=—C(CH₃)₂—C(CH₃)₂—).The NH groups of the heterocycle R¹ of the boronic acid derivatives maybe masked by any suitable protecting group (see Green, Wuts, “Protectivegroups in organic synthesis” 1999, John Wiley & Sons and referencescited therein). The corresponding protective group may be removed at anysuitable step of the synthesis. Preferably THP (tetrahydropyranyl), BOC(tertButoxycarbonyl) or PMB (para-Methoxybenzyl) are used as protectivegroups during the synthesis.

The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0)catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts like dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction is preferably carried out in a mixture of a solvent like1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with waterand in the presence of a base like potassium carbonate, sodiumbicarbonate or potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction is performed at temperatures ranging from room temperature(i.e. approx. 20° C.) to the boiling point of the respective solvent.Further on, the reaction can be performed at temperatures above theboiling point using pressure tubes and a microwave oven. The reaction ispreferably completed after 1 to 36 hours of reaction time.

The steps for the synthesis sequence giving rise to naphthyridines offormula 8 may be also interchanged using similar reaction conditions foreach step as described above. For example:

3→6→7→8

Step 8→10 (Scheme 2) Transformation of Hydroxy to Chloro Substituent

In the next step, the hydroxy-naphthyridine of formula 8 is converted tothe corresponding chloro-naphthyridine 10. This reaction is typicallyperformed using POCl₃ without any additional solvent. The reaction istypically carried out at elevated temperatures.

The steps for the synthesis sequence giving rise to naphthyridines offormula 10 may also be interchanged using similar reaction conditionsfor each step as described above. For example:

5→9→10

Step 8→11 (Scheme 2) Triflate Formation

The hydroxy-naphthyridine of the general formula 8 can be converted tothe corresponding triflate of formula 11. Typically thehydroxy-naphthyridine 8 is reacted with a triflating reagent such as forexample N-Phenylbis(trifluoromethanesulfonimide) with or without a basein an organic solvent such as for example dichloromethane.

Step 8→12 (Scheme 3) Conversion of Hydroxy to Halogen (F, Br, Cl, I)

The transformation of hydroxy-naphthyridine 8 to a halogen compound offormula 12 can be performed (for halogen=Cl) for example usingchlorinating reagents such as trichlorophosphate with or without anorganic solvent. Typically the reactions are performed at elevatedtemperatures. For halogen=Br reagents such as phosphorus tribromide orphosphorus oxytribromide can be used. For halogen=F see for example J.of Org. Chem., 2013, 78, 4184-4189. For halogen=I see for exampleJournal of Organic Chemistry, 2009, 74, 5111-5114 and referencestherein.

Step 8→13 (Scheme 3) Conversion of Hydroxy to Ethers

Hydroxy-naphthyridines of formula 8 can be converted to thecorresponding ether of general formula 13, in which R″ is C₁-C₆-alkyl or3- to 10-membered heterocycloalkyl. The reaction is performed usinghalides (preferably Cl, Br or I), tosylates, mesylates or triflates.This reaction is performed in a solvent such as for exampleacetonitrile, DMF or a 1:1 mixture of methanol and water. The reactionis performed in the presence of a base such as for example CsCO₃ orK₂CO₃. The reaction is performed at temperatures ranging from roomtemperature to the boiling point of the respective solvent. Furthermore,the reaction can be performed at temperatures above the boiling pointunder pressure. The reaction is preferably completed after 1 to 16hours.

Alternatively, the ether of general formula 13 can be synthesized via aMitsunobu reaction from an alcohol in the presence of a phosphine (suchas for example triphenylphoshine) and an azodicarboxylate (e.g.diisopropyl azodicarboxylate) in a solvent such as for example THF.

Step 8→15 (Scheme 3) Conversion of Hydroxy to Thiol

For the conversion of hydroxy-naphthyridines of formula 8 to thiols offormula 15 for example Lawesson's reagent or diphosphorus pentasulfidein an organic solvent can be used. Typically these reactions are run atelevated temperatures.

Step 15→20 (Scheme 3) Conversion of Thiol to Sulfonamide

Thiols of general formula 15 can be converted to the correspondingsulfonamides 20 via the intermediate sulfonylchlorides of formula 16 inanalogy to literature procedures. For example see European J. ofMedicinal Chemistry 2013, 60, 42-50 and references therein.

Step 15→17 (Scheme 3) Conversion of Thiol to Thioether

Thiols of formula 15 can be alkylated to the corresponding thioethers17. The reaction is performed using alkyl halides (preferably Cl, Br orI), tosylates, mesylates, or triflates. This reaction is performed in asolvent such as for example acetonitrile, DMF or a 1:1 mixture ofmethanol and water. The reaction is performed in the presence of a basesuch as for example CsCO₃ or K₂CO₃. The reaction is performed attemperatures ranging from room temperature to the boiling point of therespective solvent. Furthermore, the reaction can be performed attemperatures above the boiling point under pressure. The reaction ispreferably completed after 1 to 16 hours.

Step 17→18 (Scheme 3) Conversion of Thioether to Sulfoxide

Thioethers of formula 17 can be oxidized to the corresponding sulfoxides18. Typically an oxidizing reagent in an organic solvent is used (forexample 3-chloro-benzenecarboperoxoic acid in dichloromethane).

Step 17→19 (Scheme 3) Conversion of Thioether to Sulfone

Thioethers of general formula 17 can be oxidized to the correspondingsulfoxides 19. Typically an oxidizing reagent in an organic solvent isused (for example 3-chloro-benzenecarboperoxoic acid indichloromethane).

Step 12→17 (Scheme 4) Conversion to Thioether

Halogen compounds of the general formula 12 can be converted to thecorresponding thioethers of general formula 17 by nucleophilicsubstitution with thiols. Typically a base such as for example KOtBu,NaH, caesium carbonate, potassium carbonate in an organic solvent suchas for example tert-butanol, DMSO or DMF are used. Typically thereaction is performed at elevated temperature. See for example: Journalof Medicinal Chemistry, 2008, 51, 3466-3479 and references therein.

Step 11 or 12→21 (Scheme 4) C—N Cross Coupling Reaction or NudeophilicSubstitution

Halogen compounds of general formula 12 or triflates of general formula11 can be converted to the corresponding amines 21 by a C—N crosscoupling reaction. Typically a metal catalyst, a ligand and a base in anorganic solvent is used. For a recent review see for example: Chem. Soc.Rev., 2013, 42, 9283 or “Metal-Catalyzed Cross-Coupling Reactions (2Volume Set)”, 2004 by Armin de Meijere (Editor), Franyois Diederich(Editor) and literature references therein.

Alternatively halogen compound of general formula 12 can be converted tothe corresponding amines 21 via a nucleophilic substitution reaction.Typically nucleophilic amines in combination with a base (for exampletriethylamine, Hünig's base, potassium carbonate) in an organic solvent(for example iPrOH, DCM, DMSO, DMF) are used. See for example:Bioorganic and Medicinal Chemistry Letters, 2011, 21, 5502-5505 andreferences therein.

Step 11 or 12→22 (Scheme 4) Hydrocarbonylation

Halogen compounds of general formula 12 or triflates of general formula11 can be converted to the corresponding esters 22 by a metal catalyzedcarbonylation reaction. Typically carbonmonoxide and a palladiumcatalyst with or without a ligand (for example: palladiumacetate/1,3-bis-(diphenylphosphino)propane;bis-triphenylphosphine-palladium(II) chloride/-triphenyiphosphine), analcohol as nucleophile (for example: methanol, ethanol) in an organicsolvent (for example: DMF, methanol, ethanol) is used. See for example:Journal of Medicinal Chemistry, 2008, 51, 1649-1667 or Synthesis, 2001,7, 1098-1109 and references therein.

Step 22-23 (Scheme 4) Amide Formation

Esters of general formula 22 can be converted to the correspondingamides of general formula 23. Typically an amine is reacted incombination with a base (as for example sodium hydroxide or magnesiummethanolate) in a solvent (as for example methanol, isopropanol, water).Alternatively the ester 22 can be reacted with an amine andn-butyllithium or trimethylaluminum in an organic solvent (such as forexample THF, toluene) to form amides of formula 23. See for exampleChem. Commun., 2008, 1100-1102 and references therein.

Alternatively the ester of general formula 22 can be hydrolyzed to thecorresponding carboxylic acid (using for example KOH, water, methanol asester hydrolysis conditions) and reacted further to the correspondingamides 23 under classical amide coupling conditions. For a review foramide coupling conditions using the free carboxylic acid and an amine incombination with an activating agent see for example Chem. Soc. Rev.,2009, 38, 606-631 and references therein.

Step 11 or 12→24 (Scheme 4) Nitrile Formation

Halogen compounds of general formula 12 or triflates of general formula11 can be converted to the corresponding nitriles 24. Typically apalladium catalyst and a ligand (such as for example1,1′-bis-(diphenylphosphino)ferrocene/tris-(dibenzylideneacetone)dipalladium(0)),zinc (II) cyanide in solvent (such as for example N,N-dimethylacetamide/water) is used. See for example Tetrahedron Letters, 2006, 47,3303-3305 and references therein.

Step 11 or 12→25 (Scheme 4) C—C Cross Coupling Reaction

Halogen compounds of general formula 12 or triflates of general formula11 can be reacted with a boronic acid derivative A-B(OR)₂ to give acompound of formula 25. The group A represents C₁-C₆-alkyl,C₂-C₆-alkenyl, C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4-to 10-membered heterocycloalkenyl, phenyl, heteroaryl. The boronic acidderivative may be a boronic acid (R=—H) or an ester of the boronic acid,e.g. its isopropyl ester (R=—CH(CH₃)₂), preferably an ester derived frompinacol in which the boronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R=—C(CH₃)₂—C(CH₃)₂—).The group A of the boronic acid derivatives may be masked by anysuitable protecting group (see Green, Wuts, “Protective groups inorganic synthesis” 1999, John Wiley & Sons). The correspondingprotective group may be removed at any suitable step of the synthesis.

The coupling reaction is catalyzed by palladium catalysts, e.g. by Pd(0)catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)di-palladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts like dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate and triphenylphosphine or by[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride.

The reaction is preferably carried out in a mixture of a solvent like1,2-dimethoxyethane, dioxane, DMF, DME, THF, or isopropanol with waterand in the presence of a base like potassium carbonate, sodiumbicarbonate or potassium phosphate.

(review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim, ISBN 3-527-30991-8 and references cited therein).

The reaction is performed at temperatures ranging from room temperatureto the boiling point of the solvent. Further on, the reaction can beperformed at temperatures above the boiling point under pressure. Thereaction is preferably completed after 1 to 36 hours.

Step 25→26 (Scheme 4) Hydrogenation of Double Bond

Unsaturated derivatives of formula 25 (wherein the group A representsC₂-C₆-alkenyl, C₅-C₆-cycloalkenyl, 4- to 10-memberedheterocycloalkenyl). can be hydrogenated to the corresponding saturatedderivatives of general formula 26 (wherein the group D representsC₂-C₆-alkyl, C₅-C₆-cycloalkyl, 4- to 10-membered heterocycloalkyl).Typically hydrogen (at atmospheric or elevated pressure) is used incombination with a heterogeneous or homogeneous catalyst such as forexample palladium on charcoal in an organic solvent such as ethylacetate, methanol or acetic acid.

Step 12→27 (Scheme 4) Dehalogenation Reaction

Halides of general formula 12 can be dehalogenated for example by ahydrogenation reaction to obtain naphthyridines of general formula 27.Typically hydrogen (at atmospheric or elevated pressure), a base as forexample triethylamine and a heterogeneous metal catalyst such as forexample palladium on activated carbon in an organic solvent such as forexample ethanol, ethyl acetate, acetic acid is used.

Step 11 or 12→19 (Scheme 4) Sulfonylation Reaction

A halide of general formula 12 or a triflate of general formula 11 canbe converted to the corresponding sulfone of general formula 19 byreaction with an alkyl sulfinic acid sodium salt or aryl sulfinic acidsodium salt with a base such as for example4-(N,N-dimethlyamino)pyridine or pyridine in an organic solvent as forexample N,N-dimethyl-formamide. Typically the reaction is performed atelevated temperature. The reaction can also be mediated by copper (seefor example European Journal of Medicinal Chemistry, 2004, vol. 39,735-744).

Step 18→31 (Scheme 5) Sulfoximine Formation

Sulfoxide 18 is converted to the corresponding sulfoximine 31 in a twostep procedure. Typically, the sulfoxide 18 is converted to a protectedsulfoximine intermediate using a described procedure (Org. Lett., 2004,6, 1305-1307 and references therein). Deprotection to the sulfoximine to31 is performed using a base such as for example K₂CO₃ in methanol.Additional options to convert the sulfoxide 18 to an unprotectedsulfoximine 31 are the use of hydrazoic acid prepared in situ (e.g. J.Chem Med Chem, 2013, 8, 1021) or the use ofO-(mesitylenesulfonyl)hydroxylamine (MSH) (e.g. J. Org. Chem., 1973, 38,1239.

Step 31→38 (Scheme 5) Functionalization of the Sulfoximine Nitrogen

Functionalization of the nitrogen of sulfoximines of general formula 31can be performed using previously described methods: N-unprotectedsulfoximines of formula 31 may be reacted to give N-functionalizedderivatives of formula 38. There are multiple methods for thepreparation of N-functionalized sulfoximines by functionalization of thenitrogen of the sulfoximine group:

-   -   Alkylation: see for example: a) U. Lücking et al, US        2007/0232632; b) C. R. Johnson, J. Org. Chem. 1993, 58,        1922; c) C. Bolm et al, Synthesis 2009, 10, 1601.    -   Reaction with isocyanates: see for example: a) V J. Bauer et        al, J. Org. Chem. 1966, 31, 3440; b) C. R. Johnson et al, J. Am.        Chem. Soc. 1970, 92, 6594; c) S. Allenmark et al, Acta Chem.        Scand. Ser. B 1983, 325; d) U. Lacking et al, US2007/0191393.    -   Reaction with chloroformiates: see for example: a) P. B. Kirby        et al, DE2129678; b) DJ. Cram et al, J. Am. Chem. Soc. 1974, 96,        2183; c) P. Stoss et al, Chem. Ber. 1978, 111, 1453; d) U.        Lacking et al, WO2005/37800.    -   Reaction with bromocyane: see for example: a) D. T. Sauer et al,        Inorganic Chemistry 1972, 11, 238; b) C. Bolm et al, Org. Lett.        2007, 9, 2951; c) U. Lacking et al, WO 2011/29537.

Step 11→32 (Scheme 6)

A triflate of general formula 11 can be converted to the correspondingsulfonamide 32 under palladium catalysis in analogy to literatureprocedures. For example see J. Am. Chem. Soc., 2009, 131, 16720-16734and references therein.

Step 11→33 (Scheme 6)

A triflate of general formula 11 can be converted to the correspondingsulfoximines 33 under palladium catalysis in analogy to literatureprocedures. For example see US2001/144345.

Step 11→34 (Scheme 6)

A triflate of general formula 11 can be converted to the correspondingsililated compound 34 under palladium catalysis in analogy to literatureprocedures. For example see Org. Lett. 2007, 9, 3785-3788 and referencestherein.

Step 11→35 (Scheme 6)

A triflate of general formula 11 can be converted to the phosphonate 35under palladium catalysis in analogy to literature procedures. Forexample see US2008/9465

Step 11→36 (Scheme 6)

A triflate of general formula 11 can be converted to the phosphinate 36under palladium catalysis in analogy to literature procedures. Forexample see Adv. Synth. Cat., 2013, 355, 1361-1373 and referencestherein.

Step 11→37 (Scheme 6)

A triflate of general formula 11 can be converted to the phosphine oxide37 under palladium catalysis in analogy to literature procedures. Forexample see US2007/4648

EXPERIMENTAL SECTION

The following table lists the abbreviations used in this paragraph, andin the examples section.

Boc tert-butyloxycarbonyl BuLi Butyllithium conc. concentrated DCEDichloroethane DCM Dichloromethane DMAP N,N-Dimethylaminopyridine DMEDimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide EA Ethylacetate EtOAc Ethyl acetate EtOH Ethanol HPLC, LC high performanceliquid chromatography h hour LiHMDS Lithium bis(trimethylsilyl)amideKHMDS Potassium bis(trimethylsilyl)amide KOtBU Potassium tert-butoxidemin minute LCMS, LC-MS, LC/MS Liquid chromatography-mass spectrometryLDA Lithium diisopropylamide MS mass spectroscopy NMR nuclear magneticresonance NMO N-metylmorpholine-N-oxide NaHMDS Sodiumbis(trimethylsilyl)amide PE Petrol ether Pd(dppf)Cl₂[1,1′-Bis-diphenylphosphino- ferrocene]palladium(II) dichloride RacRacemate R_(f) Retardiation factor R_(t) Retention time sat. saturatedrt, RT Room temperature TFA Trifluoroacetic acid THF Tetrahydrofuran TLCthin-layer chromatography

Chemical names were generated using ACD/Name Batch Version 12.01 orAutonom 2000.

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available or synthesized asdescribed in literature references.

Analytical Methods LC-MS Method 1:

column: Ascentis Express C18, 2.7 μm, 3 cm×2.1 mmcolumn temp.: 30° C.injection volume: 1 μldetection: MM-ES+APCI+DAD (254 nm)fragment.potential: 50 Vmass range: 80-800 m/zmobile phase A: water/0.1% formic acidmobile phase B: methanol/0.1% formic acidsystem time delay: 0.2 mingradient:

time in min % A % B flow rate in ml/min 1.0 95 5 0.8 4.0 0 100 0.8 5.0 0100 0.8 6.0 95 5 0.8 6.5 95 5 0.8

LC-MS Method 2:

MS instrument type: Micromass Quatro Micro; HPLC instrument type:Agilent 1100 Series; UV DAD; column: Chromolith Flash RP-18E 25-2 mm;mobile phase A: 0.0375% TFA in water, mobile phase B: 0.01875% TFA inacetonitrile; gradient: 0.0 min 100% A→1.0 min 95% A→3.0 min 95% A→3.5min 5% A→3.51 min 5% A→4.0 min 95% A; flow rate: 0.8 ml/min; columntemp: 50° C.; UV detection: 220 nm & 254 nm.

LC-MS Method 3: System: MS (LBA639)

-   -   Binary Solvent Manager    -   Sample Manager    -   Organizer    -   Column Manger    -   PDA    -   ELSD        Injection volume: 1 μl

Column: Acquity UPLC BEH C18 1.7 50×2.1 mm

Eluent A1: H2O+0.1% Vol. HCOOH (99%)

-   -   A2: H2O+0.2% Vol. NH3 (32%)    -   B1: Acetonitril        Flow rate: 0.8 ml/min

Temperature: 60° C. Eluent Gradient A1+B1: 0-1.6 min 1-99% B1; 1.6-2.0min 99% B1 LC-MS Method 4:

Instrument MS: Waters ZQ; Instrument HPLC: Waters UPLC Acquity; Column:Acquity BEH C18 (Waters), 50 mm×2.1 mm, 1.7 μm; eluent A: water+0.1 vol% formic acid, eluent B: acetonitrile (Lichrosolv Merck); gradient: 0.0min 99% A-1.6 min 1% A-1.8 min 1% A—1.81 min 99% A—2.0 min 99% A;temperature: 60° C.; flow: 0.8 mL/min; UV-Detection PDA 210-400nmnm—plus fixed wavelength 254 nm; MS ESI (+), Scan region 170-800 m/z

Preparative HPLC Autopurifler: Acidic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.1% Vol. HCOOH (99%) B = MeCN Gradient: 0.00-0.50min 5% B, 25 ml/min 0.51-5.50 min 10-100% B, 70 ml/min 5.51-6.50 min100% B, 70 mL/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSOor DMF Injection: 1 × 2.5 ml Detection: DAD scan range 210-400 nm MSESI+, ESI−, scan range 160-1000 m/z

Autopurifler: Basic Conditions

System: Waters Autopurificationsystem: Pump 2545, Sample Manager 2767,CFO, DAD 2996, ELSD 2424, SQD Column: XBrigde C18 5 μm 100 × 30 mmSolvent: A = H₂O + 0.2% Vol. NH₃ (32%) B = MeCN Gradient: 0.00-0.50 min5% B, 25 ml/min 0.51-5.50 min 10-100% B, 70 ml/min 5.51-6.50 min 100% B,70 ml/min Temperature: RT Solution: max. 250 mg/max. 2.5 mL DMSO or DMFInjection: 1 × 2.5 ml Detection: DAD scan range 210-400 nm MS ESI+,ESI−, scan range 160-1000 m/z

Preparation of Intermediates Intermediate-1 Step amethyl-2-chloro-3-[1-morpholin-4-yleth-(E)-ylideneamino]isonicotinate

Under argon and at a temperature of 0° C., 2.44 ml (25.40 mmol) ofphosphorus oxychloride were added to a solution of 2.17 ml (18.8 mmol)of N-acetylmorpholine in 12 ml of absolute dichloroethane. The yellowsolution was stirred at room temperature for 30 min. 1.75 g (9.39 mmol)of methyl 3-amino-2-chloroisonicotinate were then added. The mixture wasstirred at 80° C. for 3 h. Dichloroethane was distilled off. Withoutwork-up, the residue was purified by column chromatography [Puriflashsilica gel 60 (80 g 30 μm); ethyl acetate/methanol 1:1, (300 ml)]. Inthis manner, methyl2-chloro-3-[1-morpholin-4-yleth-(E)-ylideneamino]isonicotinate wasobtained in a yield of 2.5 g (89% of theory) as a yellow oil. ¹H NMR(400 MHz, CDCl₃): δ [ppm]=1.79-1.84 (2H), 2.14 (3H), 3.66-67 (4H),3.88-3.91 (4H), 3.93 (3H), 7.77 (1H), 8.56 (2H).

Step b 8-chloro-2-(morpholin-4-yl)-[1,7]naphthyridin-4-ol

Under argon and at 0° C., 20.1 ml (20.1 mmol) of lithiumbis(trimethylsilyl)amide were added dropwise to a solution of 2.0 g (6.7mmol) of methyl2-chloro-3-[1-morpholin-4-yleth-(E)-ylideneamino]isonicotinate in 20 mlof dry N,N-dimethytformamide. The mixture was then stirred at roomtemperature for 3 h. For work-up, 2 ml of water were added and themixture was concentrated. The residue was chromatographed [Puriflashsilica gel 60 (80 g, 30 μm), ethyl acetate/methanol 1:1 (500 ml)]. 1.16g (65% of theory) of 8-chloro-2-morpholin-4-yl-[1,7]naphthyridin-4-olwere isolated as a light-yellow solid. ¹H NMR (400 MHz, DMSO): δ[ppm]=3.63-3.65 (4H), 3.72-3.74 (4H), 6.62 (1H), 7.73 (1H), 7.98 (1H),11.62 (1H).

Intermediate-22-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-ol

Under argon, 244 mg (0.30 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) and 650 mg (2.00 mmol) of caesium carbonate wereadded to a suspension of 556 mg (2.00 mmol) of1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-pyrazoleand 266 mg (1.00 mmol) of8-chloro-2-morpholin-4-yl-[1,7]naphthyridin-4-ol in 4.0 ml of absolute1,4-dioxane. The reaction mixture was stirred at 80° C. for 16 h. Thebrown reaction solution was purified via column chromatography [silicagel 60 (30 g); ethyl acetate (200 ml)]. In this manner, 206 mg (54% oftheory) of2-morpholin-4-yl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-olwere isolated as a yellow oil. LCMS (method 1): m/z: [M+H]⁺=382.3,R_(L)=3.0 min.

Intermediate-32-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yl-trifluoromethanesulphonate

Under argon, 25 μl (0.15 mmol) of diisopropylethylamine were added to asolution of 28 mg (0.07 mmol) of2-morpholin-4-yl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-oland 39 mg (0.11 mmol) of N-phenylbis(trifluoromethanesulphonimide) in3.0 ml of absolute dichloromethane. The reaction mixture was stirred atroom temperature for 16 h. The brown reaction solution was purified viacolumn chromatography [silica gel 60 (12 g, 30 μm); ethyl acetate (100ml)]. 34 mg (88% of theory) of2-morpholin-4-yl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate were isolated as a yellow oil. ¹H NMR (400MHz, CDCl₃): δ [ppm]=1.48-1.52 (1H), 1.63-1.71 (2H), 2.04-2.10 (2H),2.48-2.54 (1H), 3.62-3.75 (4H), 3.80-3.83 (4H), 3.92 (1H), 6.04-6.06(1H), 6.96 (1H), 7.10 (1H), 7.26 (1H), 7.61 (1H), 7.69 (1H), 8.53 (1H).

Intermediate-4 4,8-dichloro-2-(morpholin-4-yl)-[1,7]naphthyridine

3 g (11.3 mmol) of 8-chloro-2-(morpholin-4-yl)-[1,7]naphthyridin-4-olwere suspended in 10 ml (107 mmol) of phosphorus oxychloride, and themixture was stirred at 95° C. for 3 h. A clear brown solution wasformed. For work-up, the mixture was, with ice-cooling, carefullyadjusted to pH 8 using 5N sodium hydroxide solution. This aqueous phasewas extracted three times with in each case 50 ml of dichloromethane.The combined organic phases were dried over sodium sulphate and thenconcentrated to dryness. The resulting brown solid was triturated with10 ml of methanol, filtered off and then dried. This gave 2.48 g (77% oftheory) of 4,8-dichlori-2-(morpholin-4-yl)-[1,7]naphthyridine as alight-brown solid. LC-MS (method 1): m/z: [M+H]⁺=284.2, R_(t)=3.53 min.

Intermediate-54-chloro-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 813 mg (0.7 mmol) oftetrakis(triphenylphosphine)palladium(0) and 2.92 g (21.1 mmol) ofpotassium carbonate were added to a suspension of 2 g (7.04 mmol) of4,8-dichloro-2-(morpholin-4-yl)-[1,7]naphthyridine and 2.94 g (10.56mmol) of1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein 30 ml of dimethoxyethane and 3 ml of water. The reaction mixture wasstirred at 100° C. for 2 h. For work-up, 20 ml of sodium bicarbonatesolution were added to the mixture. The precipitated solid was filteredoff and washed with 5 ml of water. This gave 2 g (71% of theory) of4-chloro-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=400.3, R_(t)=3.62 min.

Intermediate-68-chloro-4-isopropoxy-2-(morpholin-4-yl)-1,7-naphthyridine

A suspension of 8-Chloro-2-(morpholin-4-yl)-[1,7]naphthyridin-4-ol (2.66g, 10 mmol), 2-iodopropane (2 ml, 20 mmol) and potassium carbonate (1.66g, 12 mmol) in acetonitrile (100 ml) were stirred for 8 hours at 85° C.The reaction mixture was allowed to cool to ambient temperature, thesolvent was distilled off under reduced pressure and the residue wasdissolved in water (30 ml) and dichloromethane (50 ml). The layers wereseparated and the aqueous phase was extracted with dichloromethane (3×30ml). The combined organic phases were dried over sodium sulphate and thesolvent distilled off under reduced pressure.

The residue was crystallized from methanol (10 ml) and dried. The titlecompound was obtained in 2 g as white solid. ¹H-NMR (400 MHz, DMSO-d6):δ [ppm]=1.38 (6H), 3.67-3.82 (8H), 4.99-5.12 (1H), 6.83 (1H), 7.68 (1H),7.99 (1H).

Intermediate-7 Step a 1-((R)-3-methylmorpholin-4-yl)ethanone

12.8 g (127 mmol) of (R)-3-methylmorpholine and 52.7 g (381 mmol) ofpotassium carbonate were suspended in 300 ml of dichloromethane, themixture was stirred at room temperature for 30 min, 19.9 g (254 mmol) ofacetyl chloride were added and the mixture was stirred at roomtemperature for 18 h. The conversion was monitored by NMR. For work-up,the precipitated solid was filtered off with suction and washed with 200ml of dichloromethane. The mother liquor was concentrated to dryness.17.19 g (95% of theory) of 1-[(R)-3-methylmorpholin-4-yl]ethanone wereisolated as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.23-1.35(3H), 2.04-2.08 (3H), 2.98 (1/2H), 3.40-3.49 (2H), 3.53-3.60 (1H),3.66-3.69 (1H), 3.79 (1/2H), 3.87 (1H), 4.24 (1/2H), 4.56 (1/2H).

Step b methyl2-chloro-3-[1-((R)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinate

Under argon and at a temperature of 0° C., 17.1 ml (188 mmol) ofphosphorus oxychloride were added to a solution of 9.00 g (62.8 mmol) of1-[(R)-3-methylmorpholin-4-yl]ethanone in 78 ml of absolute1,2-dichloroethane. The yellow solution was stirred at room temperaturefor 30 min. 11.7 g (62.8 mmol) of methyl 3-amino-2-chloroisonicotinatewere then added. The mixture was stirred at 80° C. for 1 h, at roomtemperature overnight and on the next day at 80° C. for another 5 h. The1,2-dichloroethane was distilled off. For work-up, the mixture was takenup in 200 ml of dichloromethane and 100 ml of water, sodium carbonatewas added slowly and a little at a time with vigorous stirring (pH=9)and the mixture was extracted three times with in each case 250 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness under reduced pressure. Inthis manner, methyl2-chloro-3-[1-((R)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinatewas obtained in a yield of 19.5 g (100% of theory) as a brown oil whichwas used without further purification in the next step. ¹H NMR (400 MHz,CDCl₃): δ [ppm]=1.37 (3H), 1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75(3H), 3.83 (3H), 3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01 (1H). LC-MS(method 1): Rt=0.23 min; MS (ESI/APCIpos) m/z=312.2 [M+H]+.

Step c 8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol

Under argon and at 0° C., a solution of 31.4 g (187 mmol) of lithiumbis(trimethylsilyl)amide dissolved in 250 ml of dry tetrahydrofuran wasadded dropwise over a period of 15 min to a solution of 19.5 g (62.8mmol) of methyl2-chloro-3-[1-((R)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinatein 600 ml of dry tetrahydrofuran. The mixture was then stirred at roomtemperature for 3 h. For work-up, 50 ml of water were carefully addedand the mixture was concentrated to dryness under reduced pressure. Theresidue was taken up in 600 ml of saturated ammonium chloride solutionand extracted four times with in each case 200 ml ofdichloromethane/isopropanol (4:1). The combined organic phases weredried over sodium sulphate, filtered and, under reduced pressure,concentrated to dryness. The residue was recrystallized from 250 ml ofacetonitrile (7.56 g). The mother liquor was concentrated and theresidue was recrystallized again from 125 ml of acetonitrile (3.65 g).11.2 g (64% of theory, 1st fraction, clean) and 2.63 g (14% of theory,2nd fraction, about 90% pure, concentrated mother liquor) of8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol wereisolated as a yellow-orange solid. ¹H NMR (400 MHz, DMSO-d₆): δ[ppm]=1.21 (3H), 3.18 (1H), 3.49 (1H), 3.65 (1H), 3.77 (1H), 3.98 (1H),4.15 (1H), 4.41 (1H), 6.59 (1H), 7.72 (1H), 7.97 (1H), 11.59 (1H). LC-MS(method 1): R_(t)=3.05 min; MS (ESI/APCIpos) m/z=280.2 [M+H]⁺.

Intermediate-84,8-dichloro-2-[(3R)-3-methylmorpholin-4-yl]-1,7-naphthyridine

0.50 g (1.8 mmol) of8-chloro-2-[(3R)-3-methylmorpholin-4-yl]-1,7-naphthyridin-4-ol weresuspended in 1.6 ml (17 mmol) of phosphorus oxychloride, and the mixturewas stirred at 95° C. for 3 h. The reaction was cooled to roomtemperature and then placed in an ice bath. The reaction was carefullyquenched by dropwise addition of NaOH (3N) until pH 9. The aqueous phasewas extracted 3 times with CH₂Cl₂. The organic layer was dried (siliconfilter) and concentrated under reduced pressure. The crude mixture wasthen stirred with MeOH and filter. The solid was dried under reducedpressure at 40° C. The desired compound was obtained without furtherpurification. ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=1.25 (3H), 3.19-3.31(1H), 3.50 (1H), 3.61-3.69 (1H), 3.74-3.81 (1H), 3.99 (1H), 4.29 (1H),4.57-4.67 (1H), 7.77-7.81 (2H), 8.14 (1H). LC-MS (Method 3): m/z:[M+H]⁺=299, R_(t)=1.24 min.

Intermediate-92-(((R)-3-methylmorpholin-4-yl)-8-([2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-ol

Under argon, 146 mg (0.18 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) and 2.33 g (7.15 mmol) of caesium carbonate wereadded to a suspension of 500 mg (1.79 mmol) of8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol and 746mg (2.68 mmol) of1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-pyrazolein 7.5 ml of absolute 1,4-dioxane. The reaction mixture was stirred at90° C. for 16 h. The brown reaction solution was purified via columnchromatography [silica gel 60 (30 g); ethyl acetate (200 ml)]. In thismanner, 506 mg (72% of theory) of2-[(R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-olwere isolated as a yellow oil. LCMS (method 1): m/z: [M+H]⁺=396.3,R_(t)=3.11 min.

Intermediate-102-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromehanesulfonate

Under argon a solution of 4.81 g (11.74 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol,6.43 g (18 mmol) N-Phenylbis(trifluoromethanesulfonimide) and 4.18 ml(24 mmol) N,N-Diisopropylethylamin in 100 ml absolute dichloromethanewas stirred for 3 days at room temperature. The solvent was distilledoff under reduced pressure and the residue was chromatographed twice[silica gel 60 (400 g); dichlormethane/methanol, 98:2/ethyl acetate].The title compound was obtained in 2.6 g (42% of theory) as yellowsolid. LC-MS (method 1): m/z: [M+H]+=528.2, Rt=4.00 min.

Intermediate-11 Step a 1-((S)-3-methylmorpholin-4-yl)ethanone

12.8 g (127 mmol) of (S)-3-methylmorpholine and 52.7 g (381 mmol) ofpotassium carbonate were suspended in 300 ml dichloromethane, themixture was stirred at room temperature for 30 min, 19.9 g (254 mmol) ofacetyl chloride were added with ice bath cooling and the mixture wasstirred at room temperature for 7 d. The potassium carbonate wasfiltered off with suction and washed. With ice bath cooling, 43 ml (248mmol) of N,N-diisopropylethylamine were added to the mother liquor, andthe mixture was stirred at room temperature for 1 h. The solution waswashed three times with in each case 200 ml of water, dried over sodiumsulphate, filtered and concentrated to dryness under reduced pressure.9.39 g (69% of theory) of 1-((S)-3-methylmorpholin-4-yl)ethanone wereisolated as a brown oil. ¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.23-1.35(3H), 2.04-2.08 (3H), 2.98 (1/2H), 3.40-3.49 (2H), 3.53-3.60 (1H),3.66-3.69 (1H), 3.79 (1/2H), 3.87 (1H), 4.24 (1/2H), 4.56 (1/2H).

Step b methyl2-chloro-3-[1-((S)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinate

Under argon and at a temperature of 0° C., 18.3 ml of (197 mmol) ofphosphorus oxychloride were added to a solution of 9.39 g (65.6 mmol) of1-((S)-3-methylmorpholin-4-yl)ethanone in 83 ml of absolute1,2-dichloroethane. The yellow solution was stirred at room temperaturefor 30 min. 12.37 g (65.6 mmol) of methyl 3-amino-2-chloroisonicotinatewere then added. The mixture was stirred at 80° C. for 5 h. The1,2-dichloroethane was distilled off. For work-up, the mixture was takenup in 200 ml of dichloromethane and 100 ml of water, with vigorousstirring, by slowly adding, a little at a time, solid sodium carbonate,the pH was adjusted to pH=9 and the mixture was then extracted threetimes with in each case 250 ml of dichloromethane. The combined organicphases were dried over sodium sulphate and then concentrated underreduced pressure. In this manner, methyl2-chloro-3-[1-((S)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinatewas obtained in a yield of 19.2 g (94% of theory) as a brown oil whichwas reacted further without further purification. ¹H NMR (400 MHz,CDCl₃): δ [ppm]=1.37 (3H), 1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75(3H), 3.83 (3H), 3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01(1H). LC-MS(method 1): R_(t)=0.23 min; MS (ESI/APCIpos) m/z=312.2 [M+H]⁺.

Step c 8-chloro-2-((S)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol

Under argon at 0° C., a solution of 30.8 g (184 mmol) of lithiumbis(trimethylsilyl)amide, dissolved in 250 ml of dry tetrahydrofuran,was added dropwise over a period of 15 min to a solution of 19.2 g (61.5mmol) of methyl2-chloro-3-[1-(S)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinatein 600 ml of dry tetrahydrofuran. The mixture was then stirred at roomtemperature for 3 h. For work-up, 50 ml of water were carefully addedand the mixture was concentrated under reduced pressure. The residue wastaken up in 600 ml of saturated ammonium chloride solution and extractedfour times with in each case 200 ml of dichloromethane/isopropanol(4:1). The combined organic phases were dried over sodium sulphate,filtered and, under reduced pressure, concentrated to dryness. Theresidue was recrystallized from 250 ml of acetonitrile (5.7 g). Themother liquor was concentrated and the residue was recrystallized againfrom 125 ml of acetonitrile (5.0 g). 10.7 g (62% of theory, 1stfraction, clean) and 4.53 g (24% of theory, 2nd fraction, about 90%pure, concentrated mother liquor) of8-chloro-2-((S)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol wereisolated as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (3H),3.18 (1H), 3.49 (1H), 3.65 (1H), 3.76 (1H), 3.98 (1H), 4.15 (1H), 4.40(1H), 6.60 (1H), 7.72 (1H), 7.97 (1H), 11.6 (1H). LC-MS (method 1):R_(t)=3.05 min; MS (ESI/APCIpos) m/z=280.2 [M+H]⁺.

Step d2-((S)-3-methylmorpholin-4-yl)-8-[(2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-ol

Under argon, 583 mg (0.75 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) and 9.31 g (28.6 mmol) of caesium carbonate wereadded to a suspension of 2.00 g (7.15 mmol) of8-chloro-2-((S)-3-methyl-morpholin-4-yl)-[1,7]naphthyridin-4-ol and 2.98g (10.7 mmol) of 1-(tetrahydropyran-2H-pyran-2-yl)-1H-pyrazol-5-boronicacid pinacol ester in 80 ml of absolute 1,4-dioxane. The reactionmixture was degassed three times and stirred at 85° C. for 3 h. Since,according to LC/MS, conversion was incomplete and there was no furtherconversion (starting material:product about 40:60), another 2 g of1-(tetrahydropyran-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacolester, 200 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) and 3 g of caesium carbonate were added to thereaction solution and the mixture was stirred at 85° C. for 1 h. Thesolvent was distilled off and 100 ml of saturated ammonium chloridesolution were added to the residue. The aqueous phase was extracted fourtimes with in each case 100 ml of dichloromethane/isopropanol 4:1. Thecombined organic phases were dried over sodium sulphate and thenconcentrated to dryness under reduced pressure. The residue waschromatographed [silica gel 60 (2×80 g, 50 μm); dichloromethane/methanol96:4 to 90:10]. This gave 402 mg (13% of theory) of2-((S)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-olas a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ [ppm]=1.18 (3H),1.44-1.61 (3H), 1.91-2.00 (2H), 2.32-2.40 (1H), 3.09-3.18 (1H),3.21-3.28 (1H), 3.45 (1H), 3.60-3.76 (3H), 3.91-4.02 (2H), 4.30 (1H),6.09 (1H), 6.59 (1H), 6.91 (1H), 7.59 (1H), 7.77 (1H), 8.33 (1H), 11.46(1H). LC-MS (method 1): R_(t)=3.08 min; MS (ESI/APCIpos) m/z=396.2[M+H]⁺.

Intermediate-128-chloro-2-[(3R)-3-methylmorpholin-4-yl]-4-(propan-2-yloxy)-1,7-naphthyridine

2.96 g (21.5 mmol) of potassium carbonate were added to a solution of 5g (18 mmol) of 8-chloro-2-(morpholin-4-yl)-[1,7]naphthyridin-4-ol and3.57 ml (36 mmol) of 2-iodopropane in 50 ml of dry acetonitrile. Thesuspension was stirred at 85° C. for 2 h. The course of the reaction wasmonitored by LCMS. 100 ml of water were added to the mixture. Theaqueous phase was extracted three times with in each case 50 ml ethylacetate. The combined organic phases were dried over sodium sulphate andthen concentrated to dryness. The residue was chromatographed [silicagel 60 (80 g, 30 μm); ethyl acetate (500 ml)]. 4 g (70% of theory) of8-chloro-2-[(3R)-3-methylmorpholin-4-yl]-4-(propan-2-yloxy)-1,7-naphthyridinewere obtained as a beige solid. LC-MS (method 1): m/z: [M+H]⁺=322.2,R_(t)=3.79 min.

Intermediate-13 Step a4,8-dichloro-2-(morpholin-4-yl)-[1,7]naphthyridine

3 g (11.3 mmol) of 8-chloro-2-(morpholin-4-yl)-[1,7]naphthyridin-4-olwere suspended in 10 ml (107 mmol) of phosphorus oxychloride, and themixture was stirred at 95° C. for 3 h. A clear brown solution wasformed. For work-up, the mixture was, with ice-cooling, carefullyadjusted to pH 8 using 5N sodium hydroxide solution. This aqueous phasewas extracted three times with in each case 50 ml of dichloromethane.The combined organic phases were dried over sodium sulphate and thenconcentrated to dryness. The resulting brown solid was triturated with10 ml of methanol, filtered off and then dried. This gave 2.48 g (77% oftheory) of 4,8-dichlori-2-(morpholin-4-yl)-[1,7]naphthyridine as alight-brown solid. LC-MS (method 1): m/z: [M+H]⁺=284.2, R_(t)=3.53 min.

Step b4-chloro-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 813 mg (0.7 mmol) oftetrakis(triphenylphosphine)palladium(0) and 2.92 g (21.1 mmol) ofpotassium carbonate were added to a suspension of 2 g (7.04 mmol) of4,8-dichloro-2-(morpholin-4-yl)-[1,7]naphthyridine and 2.94 g (10.56mmol) of1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein 30 ml of dimethoxyethane and 3 ml of water. The reaction mixture wasstirred at 100° C. for 2 h. For work-up, 20 ml of sodium bicarbonatesolution were added to the mixture. The precipitated solid was filteredoff and washed with 5 ml of water. This gave 2 g (71% of theory) of4-chloro-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=400.3, R_(t)=3.62 min.

Intermediate-14 Step a 1-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethanone

(3R,5S)-3,5-Dimethylmorpholine (0.50 g, 4.3 mmol, 1 eq.) was solubilizedin pyridine (8.6 mL, 0.11 mol, 25 eq.) and acetic anhydride (4.0 mL, 42mmol, 10 eq.) was added. The reaction was stirred for 16 hours at roomtemperature. The reaction mixture was then concentrated under reducedpressure and the desired product was obtained in 95% yield (0.64 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 1.22 (6H), 2.00 (3H), 3.44 (2H), 3.65(2H), 4.00 (2H). LC-MS (Method 3): m/z: [M+H]⁺=158, R_(t)=0.57 min.

Step b methyl2-chloro-3-[(E)-{1-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethylidene}amino]isonicotinate

1-[(3R,5S)-3,5-Dimethylmorpholin-4-yl]ethanone (0.54 g, 3.4 mmol, 2.3eq.) was solubilized in DCE (2.7 mL) and the reaction mixture was cooledto 0° C. POCl₃ (0.46 mL, 4.3 mmol, 3.3 eq.) was added slowly and thereaction was warmed up to rt. After 30 minutes, methyl3-amino-2-chloroisonicotinate (0.28, 1.5 mmol, 1 eq.) was added in oneportion and the mixture was stirred at 80° C. After 6 hours, thereaction was cooled to room temperature and the solvent was removedunder reduced pressure. The crude mixture was diluted with CH₂Cl₂ andwashed three times with sat. NaHCO₃. The organic phase was dried (MgSO₄)and concentrated under reduced pressure. The crude mixture was purifiedby flash chromatography (gradient: 100% hexane to 100% EtOAc). Thedesired product was obtained in 58% yield (0.28 g). ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 1.29 (3H), 1.33 (3H), 1.77 (3H), 3.56 (2H), 3.72 (2H),3.77 (3H), 4.06-4.24 (2H), 7.56 (1H), 8.01 (1H). LC-MS (Method 3): m/z:[M+H]⁺=326, R_(L)=0.85 min.

Step c8-chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-naphthyridine

Methyl2-chloro-3-[(E)-{1-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethylidene}amino]isonicotinate(0.28 g, 0.86 mmol, 1 eq.) was solubilised in dry THF (6 mL) under inertatmosphere (Argon). The reaction mixture was cooled to 0° C. and asolution of LiHMDS (1.0 M in THF, 2.5 mL, 2.6 mmol, 3 eq.) was addedslowly. The reaction mixture was stirred for 16 h at room temperature.The reaction was quenched with H₂O and concentrated under reducedpressure. The crude8-chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol(0.36 g) was used in the next step without further purification. CH₃CN(10 mL) was added to8-chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol(0.20 g, 0.68 mmol, 1 eq.). 2-Iodopropane (0.13 mL, 1.4 mmol, 2 eq.) andK₂CO₃ (0.14 g, 0.81 mmol, 1.2 eq.) were sequentially added to thesuspension. The reaction mixture was stirred at 85° C. for 16 h. Thereaction was cooled to room temperature and diluted with EtOAc andwashed three times with H₂O. The organic phase was dried (MgSO₄) andconcentrated under reduced pressure. The desired product was obtainedwithout further purification in 60% yield over two steps. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm]: 1.31 (6H), 1.39 (6H), 3.64 (2H), 3.83 (2H), 4.54(2H), 5.04 (1H), 6.66 (1H), 7.68 (1H), 7.97 (1H). LC-MS (Method 3): m/z:[M+H]⁺=336, R_(t)=1.39 min.

Intermediate-15 Step a 1-[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethanone

(3R,5R)-3,5-Dimethylmorpholine (0.50 g, 4.3 mmol, 1 eq.) was solubilizedin pyridine (8.6 mL, 0.11 mmol, 25 eq.) and acetic anhydride (4.0 mL,0.42 mmol, 10 eq.) was added. The reaction was stirred for 16 hours atroom temperature. The reaction mixture was then concentrated underreduced pressure and the desired product was obtained in quantitativeyield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.26 (6H), 2.00 (3H), 3.43-3.59(2H), 3.83-3.97 (4H). LC-MS (Method 3): m/z: [M+H]⁺=158, R_(t)=0.56 min.

Step b methyl2-chloro-3-[(E)-{1-[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethylidene}amino]isonicotinate

1-[(3R,5R)-3,5-Dimethylmorpholin-4-yl]ethanone (0.70 g, 4.4 mmol, 2.3eq.) was solubilized in DCE (10 mL) and the reaction mixture was cooledto 0° C. POCl₃ (0.59 mL, 6.4 mmol, 3.3 eq.) was added slowly and thereaction was warmed up to rt. After 30 minutes, methyl3-amino-2-chloroisonicotinate (0.36 g, 1.9 mmol, 1 eq.) was added in oneportion and the mixture was stirred at rt. After 48 hours, the reactionwas quenched with sat. NaHCO₃ and extracted three times with CH₂Cl₂. Theorganic phase was dried (MgSO₄) and concentrated under reduced pressure.The crude mixture was purified by flash chromatography (gradient: 100%hexane to 100% EtOAc). The desired product was obtained in 18% yield(0.12 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.26 (3H), 1.33 (3H), 1.79(3H), 3.55 (2H), 3.77 (3H), 3.89-4.00 (4H), 7.54-7.58 (1H), 8.02-8.06(1H).

Step c8-chloro-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-naphthyridine

Methyl2-chloro-3-[(E)-{1-[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethylidene}amino]isonicotinate(0.12 g, 0.36 mmol, 1 eq.) was solubilised in dry THF (2.5 mL) underinert atmosphere (Argon). The reaction mixture was cooled to 0° C. and asolution of LiHMDS (1.0 M in THF, 1.1 mL, 1.1 mmol, 3 eq.) was addedslowly. The reaction mixture was stirred for 16 h at room temperature.The reaction was quenched with H₂O and concentrated under reducedpressure The crude8-chloro-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol(0.36 g) was used in the next step without further purification. CH₃CN(6.8 mL) was added to8-chloro-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-1,7-naphthyridin-4-ol(0.14 g, 0.46 mmol, 1 eq.). 2-Iodopropane (0.10 mL, 0.90 mmol, 2 eq.)and K₂CO₃ (74 mg, 0.55 mmol, 1.2 eq.) were sequentially added to thesuspension. The reaction mixture was stirred at 85° C. for 48 h. Thereaction was cooled to room temperature and diluted with H₂O, extractedthree times with CH₂Cl₂ and washed with sat. NaCl. The organic phase wasdried (silicon filter) and concentrated under reduced pressure. Thedesired product was obtained without further purification in 52% yieldover two steps (81 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]: 1.26 (6H),1.39 (6H), 3.58-3.64 (2H), 3.99-4.04 (2H), 4.17-4.25 (2H), 4.97-5.07(1H), 6.85 (1H), 7.73 (1H), 8.06 (1H). LC-MS (Method 3): m/z:[M+H]⁺=336, R_(t)=1.38 min.

Intermediate-16 Step a 1-bromo-3-(methylsulfinyl)benzene

To a solution of (3-bromophenyl)(methyl)sulfane (50.0 g, 0.246 mol) inCH₃CN (500 mL) was added FeCl₃ (1.2 g, 7.4 mmol) with stirring. Afterthe addition, the mixture was stirred at room temperature for 10 min andthen cooled to 0° C. H₅IO₆ (62.0 g, 0.272 mol) was added in portions andthen the mixture was stirred at 0° C. for 1 h. TLC (PE:EA=3:1,R_(f)=0.4) showed the most of starting material was consumed. Thereaction mixture was quenched by the addition of saturated aqueous NH₄Cl(1.0 L) and extracted with EA (300 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give 1-bromo-3-(methylsulfinyl)benzene (55.0g) as yellow oil, which was used directly in the next step withoutfurther purification.

Step b 1-bromo-3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)

To a suspension of 1-bromo-3-(methylsulfinyl)benzene (55.0 g, 0.251mol), ethyl carbamate (45.0 g, 0.505 mol), MgO (40.3 g, 1.0 mol) andRh₂(OAc)₄ (2.6 g, 7.6 mmol) in DCM (600 mL) was added PhI(OAc)₂ (122.0 g0.378 mol) carefully under N₂. The mixture was stirred at roomtemperature for 5 days. TLC (PE:EA=1:1, R_(f)=0.8) showed the most ofstarting material was consumed. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give the crudecompound, which was chromatographed on silica gel (PE:EA=20:1-5:1) togive 1-bromo-3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene (55.0g, 81.4% of theory) as white solid. ¹H NMR (400 MHz, CDCl₃): δ=8.15-8.14(1H), 7.94-7.92 (1H), 7.81-7.80 (1H), 7.51-7.47 (1H), 4.13-4.08 (2H),3.32 (3H), 1.25 (3H).

Step c 4,4,5,5-tetramethyl-(3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane

To a solution of1-bromo-4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene (55.0 g,0.18 mol) in anhydrous dioxane (600 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (53.0 g,0.209 mol), KOAc (35.3 g, 0.34 mol) and Pd(dppf)Cl₂ (4.0 g, 5.47 mmol)under N₂. After the addition, the mixture was stirred at 80° C. for 4 h.TLC (PE:EA=1:1, R_(f)=0.6) showed the most of starting material wasconsumed. The mixture was filtered and to the filtrate was added CH₃COOH(20.0 g, 0.33 mol) and Pinacol (30.0 g, 0.253 mol). The resultingmixture was stirred at room temperature for 18 h. The mixture wasconcentrated and chromatographed on silica gel (PE:EA=0:1˜5:1) to givethe crude, which was washed by PE/EA (100 mL×2, PE:EA=1:10) to give4,4,5,5-tetramethyl-(3-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane(35.0 g, 55.2% of theory) as white solid. ¹H NMR (400 MHz, MeOD-d₄):δ=8.40 (1H), 8.09-8.07 (1H), 7.61-7.58 (1H), 4.13-4.07 (2H), 3.32 (3H),1.35 (12H), 1.25-1.22 (3H). LC-MS method 2: (ES-API) m/z=272.0(M+H−82)⁺.

Intermediate-17 Step a 1-bromo-4-(methylsulfinyl)benzene

To a solution of (3-bromophenyl)(methyl)sulfane (100.0 g 0.492 mol) inCH₃CN (500 mL) was added FeCl₃ (2.4 g, 14.8 mmol) with stirring. Afterthe addition, the mixture was stirred at room temperature for 10 min andthen cooled to 0° C. H₅IO₆ (124.2 g, 0.545 mol) was added in portionsand the mixture was stirred at 0° C. for 1 h. TLC (PE:EA=5:1, R_(f)=0.2)showed the most of starting material was consumed. The reaction mixturewas quenched by the addition of saturated aqueous NH₄Cl (1.0 L) andextracted with EA (300 mL×4). The organic layers were washed with brine(300 mL), dried over Na₂SO₄ and concentrated. The residue was purifiedby chromatography on silica gel (PE/EA=20:1˜5:1) to give1-bromo-4-(methylsulfinyl)benzene (103.0 g, 95.5% of theory) as a whitesolid.

Step b 1-bromo-4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene

To a suspension of 1-bromo-4-(methylsulfinyl)benzene (100.0 g, 0.456mol), ethyl carbamate (77.0 g, 0.864 mol), MgO (73.4 g 1.821 mol) andRh₂(OAc)₄ (4.7 g 10.63 mmol) in DCM (1.5 L) was added PhI(OAc)₂ (221.5g, 0.688 mol) carefully under N₂. The mixture was stirred at roomtemperature for 7 days. TLC (PE:EA=1:1, R_(f)=0.7) showed the most ofstarting material was consumed. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by chromatography on silica gel (PE/EA=20:1˜5:1) to give1-bromo-4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene (95.0 g,68.0% of theory) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ=7.87-7.85(2H), 7.76-7.74 (2H), 4.13-4.08 (2H), 3.30 (3H), 1.28-1.22 (3H).

Step c4,4,5,5-tetramethyl-(4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)phenyl)-1,3,2-dioxaborolane

To a solution of1-bromo-4-(N-(ethoxycarbonyl)-S-methylsulfonimidoyl)benzene (95.0 g0.310 mol) in anhydrous dioxane (1.5 L) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (95.0 g,0.374 mol), KOAc (61.0 g 0.622 mol) and Pd(dppf)Cl₂(7.0 g, 9.57 mmol)under N₂. After the addition, the mixture was stirred at 80° C. for 18h. The mixture was filtered and to the filtrate was added CH₃COOH (18.0g, 0.30 mol) and pinacol (18.0 g, 0.152 mol). The mixture was stirred atroom temperature for 18 h. The mixture was concentrated and the residuewas first purified by chromatography on silica gel (PE/EA=20:1˜5:1) andthen washed by EA/PE (100 mL×2, EA/PE=1:10) to give the title compound(87.0 g, 79.5% of theory) as a white solid. ¹H NMR (400 MHz, MeOD-d4):δ=8.04-7.97 (4H), 4.13-4.06 (2H), 3.30 (3H), 1.36 (12H), 1.25-1.21 (3H).LC-MS method 2: (ES-API) m/z=272.1 (M+H−82)⁺.

Intermediate-184-chloro-2-[(3R)-3-methylmorpholin-4-yl-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Intermediate-8 (0.5 g, 1.7 mmol),1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.47 g, 1.7 mmol) and PdCl₂(PPh₃)₂(0.12 g, 0.17 mmol) were solubilisendin DME (15 mL). Potassium carbonate (2.5 mL, 5.0 mmol, 2M aq. Solution)was added and the reaction was heated for 10 minutes under microwaveirradiation at 130° C. The reaction mixture was dried by filtrationthrough a silicon filter and concentrated under reduced pressure. Thecrude material was purified by Flash column chromatography (Hexane\ethylacetate). The title compound was obtained in 45% yield (0.5 g).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21 (dd, 3H), 1.40-1.64 (m, 3H),1.90-2.03 (m, 2H), 2.30-2.39 (m, 1H), 3.15-3.28 (m, 2H), 3.41-3.52 (m,1H), 3.57-3.78 (m, 3H), 3.92-3.99 (m, 1H), 4.12 (t, 1H), 4.44-4.54 (m,1H), 5.99-6.09 (m, 1H), 6.92 (dd, 1H), 7.62 (s, 1H), 7.76 (d, 1H), 7.83(d, 1H), 8.49 (d, 1H).

Preparation of the compounds of the present Invention Example 14-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideStep a4-[(2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

Under argon, 48 mg (0.06 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 761 mg (2.34 mmol) of caesiumcarbonate were added to a suspension of 300 mg (0.58 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in7.5 ml of absolute dioxane. The reaction mixture was stirred at 100° C.for 3 h. The mixture was chromatographed directly without work-up[silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)]. This gave 280 mg(81% of theory) of4-[(2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=591.3, R_(t)=3.43 min.

Step b4-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

185 mg (0.31 mmol) of4-[(2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere dissolved in 20 ml of ethanol, and 4 ml of (8 mmol) of 2Nhydrochloric acid were added. After 1 h, LCMS showed complete removal ofthe protective group. Ethanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. This gave158 mg (99% of theory) of4-[(2-(Morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]-naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideas a colourless solid. m.p. 230-232° C. ¹H NMR (400 MHz, DMSO-d₆): δ[ppm]=1.12-1.15 (3H), 3.56 (3H), 3.80 (8H), 3.91-4.00 (2H), 7.33-7.35(1H), 7.42 (1H), 7.57 (1H), 7.65 (1H), 7.88-7.90 (2H), 8.15-8.17 (2H),8.35-8.36 (1H), 13.40 (1H). LC-MS (method 1): m/z: [M+H]⁺=507.3,R_(t)=2.93 min.

Example 24-[(2-(Morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximide

158 mg (0.312 mmol) of4-[(2-(morpholin-4-yl)-8-[-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere suspended in 10 ml of sodium methoxide (33%), and the mixture wasstirred at 60° C. for 30 min. For work-up, 20 ml of water were added andthe mixture was then extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and concentrated. The solid formed was triturated with 5 ml ofmethanol, filtered off and dried. This gave 88 mg (65% of theory) of4-[(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideas a yellow solid. m.p. 271-273° C. ¹H NMR (400 MHz, DMSO-d₆): δ[ppm]=3.17 (3H), 3.80 (8H), 4.35 (1H), 7.35-7.37 (1H), 7.42 (1H), 7.54(1H), 7.65 (1H), 7.79-7.82 (2H), 8.12-8.14 (2H), 8.34-8.35 (1H), 13.40(1H). LC-MS (method 1): m/z: [M+H]⁺=435.3, R_(t)=2.62 min.

Example 34-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 16 mg (0.019 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 100 mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 78 mg (0.39 mmol)[6-(methylsulfonyl)pyridin-3-yl]boronic acid in 1.4 ml dioxane and 254mg (0.78 mmol) caesium carbonate. The mixture was stirred at 110° C. for4 hours. After cooling, the reaction mixture was diluted with ethylacetate and an aqueous solution of sodium chloride. The mixture wasextracted with ethyl acetate (2×) and the combined organic phases werefiltered using a Whatman filter. The organic phase was concentrated andthe crude product (168 mg) was used without further purification.

Step b4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.37 ml (0.73 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 165 mg crude4-[6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.5 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: acidic conditions) to give 9 mg (0.02 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.40 (3H), 3.82(8H), 7.38 (1H), 7.43 (1H), 7.66 (1H), 7.70 (1H), 8.26 (1H), 8.36 (1H),8.40 (1H), 9.01 (1H), 13.42 (1H).

Example 44-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-([1,7]naphthyridineStep a4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 40 mg (0.05 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 635 mg (1.95 mmol) of caesiumcarbonate were added to a suspension of 250 mg (0.49 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 205 mg (0.97 mmol) of3,6-dihydro-2H-pyran-4-boronic acid and pinacol ester in 5.0 ml ofabsolute dioxane. The reaction mixture was stirred at 110° C. for 4 h.The mixture was chromatographed directly without work-up [silica gel 60(25 g, 30 μm); ethyl acetate (100 ml)]. This gave 55 mg (25% of theory)of4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=448.4, R_(t)=3.43 min.

Step b4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to50 mg (0.11 mmol) of4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After one hour of stirring at room temperature, the trifluoroacetic acidwas distilled off and the residue was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. The residuewas chromatographed [silica gel 60 (25 g, 30 μm); ethyl acetate (100ml)]. This gave 15 mg (37% of theory) of4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 233-235° C. ¹H NMR (400 MHz, DMSO): δ[ppm]=3.76-3.78 (10H), 3.90-3.92 (2H), 4.29-4.31 (2H), 5.99 (1H), 7.38(2H), 7.61 (1H), 7.66-7.67 (1H), 8.35-8.36 (1H), 13.35 (1H). LC-MS(method 1): m/z: [M+H]⁺=364.3, R_(t)=2.71 min.

Example 54-(4-(N,S-dimethylsulfonimidoyl)phenyl)-2-[morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[4-(N,S-dimethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

2-[Morpholin-4-yl]-4-[4-(S-methylsulfonimidoyl)phenyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(83 mg, 0.16 mmol, 1 eq.) was solubilized in THF (3 mL) and NaH (60% inmineral oil, 15 mg, 0.38 mmol, 2.4 eq). The reaction mixture was stirredfor 30 minutes at rt and iodomethane (35 μL, 0.56 mmol, 3.5 eq.) wasadded. The reaction was stirred for 16 hours at rt and then quenched byaddition of H₂O. The aqueous phase was extracted 3 times with CH₂Cl₂ andthe organic phase was dried (MgSO₄), filtered and concentrated underreduced pressure. The crude material was purified by preparative HPLC(basic) and the desired compound was obtained in 63% yield (57 mg).¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]: 1.40-1.66 (3H), 1.92-2.05 (2H),2.34-2.45 (1H), 2.55 (3H), 3.22 (3H), 3.24-3.30 (1H), 3.72 (9H),6.06-6.12 (1H), 6.94 (1H), 7.43 (1H), 7.52 (1H), 7.64 (1H), 7.85 (2H),8.03 (2H), 8.39 (1H). LC-MS (Method 3): m/z: [M+H]⁺=533, R_(t)=0.94 min.

Step b4-(4-(N,S-dimethylsulfonimidoyl)phenyl)-2-[morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-[4-(N,S-Dimethylsulfonimidoyl)phenyl]-2-[morpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(57 mg, 0.11 mmol, 1 eq.) was solubilised in CH₂Cl₂ (1.5 mL) and H₂O(1.5 mL). Formic acid (1 mL) was added and the reaction mixture wasstirred for 1 h at rt. The mixture was neutralised with sat. NaHCO₃ andthe aqueous phase was extracted 3 times with CH₂Cl₂. The organic phasewas dried (silicon filter) and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography (gradientfrom 100% Hex to 100% EtOAc). The title compound was obtained in 70%yield (46 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 2.55 (3H), 3.22 (3H),3.80 (8H), 7.38 (1H), 7.43 (1H), 7.57 (1H), 7.64 (1H), 7.84 (2H), 8.03(2H), 8.35 (1H), 13.42 (1H). LC-MS (Method 3): m/z: [M+H]⁺=449,R_(t)=0.91 min.

Example 64-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[4-methyl-6-(methylsulfonyl)pyrdin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 16 mg (0.019 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 100 mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 116 mg (0.39 mmol)4-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinein 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixturewas stirred at 130° C. for 10 minutes in a microwave oven. Aftercooling, the reaction mixture was diluted with DCM and filtered using aWhatman filter. The organic phase was concentrated and the crude product(164 mg) was used without further purification.

Step b4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.31 ml (0.61 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 164 mg crude4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.0 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preperative HPLC(Autopurifier: basic conditions) to give 31 mg (0.07 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=2.24 (3H), 3.37 (3H),3.80 (8H), 7.00 (1H), 7.45 (1H), 7.65 (2H), 8.19 (1H), 8.30 (1H), 8.69(1H), 13.44 (1H).

Example 74-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 25 mg (0.03 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 391 mg (1.2 mmol) of caesiumcarbonate were added to a suspension of 154 mg (0.3 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonateand 169 mg (0.6 mmol) of 4-methylsulphonylphenylboronic acid pinacolester in 3.0 ml of absolute dioxane. The reaction mixture was stirred at90° C. for 2 h. The mixture was chromatographed directly without work-up[silica gel 60 (12 g, 30 μm); ethyl acetate (100 ml)]. This gave 110 mg(71% of theory) of4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow foam. LC-MS (method 1): m/z: [M+H]⁺=520.3, R_(t)=3.38 min.

Step b4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 2 ml of (26 mmol) of trifluoroacetic acid were addedto 110 mg (0.21 mmol) of4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 3 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed using a rotary evaporator and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. 5 ml of methanol wereadded to the residue. The resulting precipitated solid was filtered offusing a frit and then dried. This gave 75 mg (81% of theory) of4-(4-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 260-262° C. ¹H NMR (400 MHz, DMSO, δ ppm): 3.33(3H), 3.80 (8H), 7.36 (1H), 7.40 (1H), 7.56 (1H), 7.67 (1H), 7.86 (2H),8.14 (2H), 8.33 (1H), 13.40 (1H).

Example 84-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride Step a4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 30 mg (0.04 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 482 mg (1.48 mmol) of caesiumcarbonate were added to a suspension of 190 mg (0.37 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 148 mg (0.74 mmol) of2-methanesulphonylphenylboronic acid in 2.0 ml of absolutedimethylformamide. The reaction mixture was stirred at 90° C. for 2 h.The mixture was chromatographed directly without work-up [silica gel 60(25 g, 30 μm); chloroform/methanol 95:5 (100 ml)]. This gave 60 mg (31%of theory) of4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=520.3, R_(t)=2.92 min.

Step b4-(2-methanesulphonylpheyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to60 mg (0.12 mmol) of4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 10 min, the trifluoroacetic acid was distilled off and the residuewas adjusted to pH 7 using sodium bicarbonate solution. The aqueousphase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (12 g, m); chloroform/methanol 95:5 (100ml)]. This gave 20 mg (40% of theory) of4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-1H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=436.2, R_(t)=2.72 min.

Step c4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride

20 mg (0.046 mmol) of4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinewere dissolved in 3 ml of 2-butanol, and 18 μl of trimethylchlorosilanewere added. The mixture was stirred in the open vessel at roomtemperature for 1 h. The solid formed was filtered off with suction anddried. This gave 15 mg (69% of theory) of4-(2-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride as a yellow solid. m.p. 173-175° C. ¹H NMR (400 MHz,CD₃OD, δ ppm): 3.05 (3H), 3.87-3.97 (8H), 7.36 (1H), 7.56-7.58 (1H),7.72 (1H), 7.87 (1H), 7.89-7.95 (2H), 7.99 (1H), 8.19 (1H), 8.29 (1H),8.29-8.31 (1H). LC-MS (method 1): m/z: [M+H]⁺=436.2, R_(t)=2.72 min.

Example 9 dimethyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}phosphonateStep a dimethyl(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)phosphonate

Under argon, 12 mg (0.015 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 75 mg (0.15 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 91 mg (0.29 mmo) dimethyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]phosphonate in1.1 ml dioxane and 190 mg (0.58 mmol) caesium carbonate. The mixture wasstirred at 110° C. for 150 minutes. After cooling, the reaction mixturewas diluted with ethyl acetate and an aqueous solution of sodiumchloride. The mixture was extracted with ethyl acetate (2×) and thecombined organic phases were filtered using a Whatman filter. Theorganic phase was concentrated and the residue was purified by columnchromatography (ethyl acetate) to give 53 mg (0.10 mmol) of the desiredproduct.

Step b dimethyl{4[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}phosphonate

0.11 ml (0.22 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 53 mg dimethyl(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)phosphonatein 0.4 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. Aqueous sodium bicarbonate solution was addedand the mixture was extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and concentrated togive 38 mg (0.08 mmol) of the desired product. ¹H-NMR (400 MHz, CDCl₃):δ[ppm]=3.83 (4H), 3.87 (3H), 3.89 (3H), 3.98 (4H), 7.20 (1H), 7.39 (2H),7.62 (2H), 7.78 (1H), 8.00 (1H), 8.04 (1H), 8.44 (1H).

Example 104-Isopropenyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-isopropenyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 24 mg (29 μmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 286 mg (0.88 mmol) of caesiumcarbonate were added to a suspension of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 483 mg (1.46 mmol) oftributylisopropenylstannane in 2.0 ml of absolute dioxane. The reactionmixture was stirred at 110° C. for 16 h. 20 ml of water were added tothe mixture. The aqueous phase was extracted three times with in eachcase 20 ml of dichloromethane. The combined organic phases were driedover sodium sulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (12 g, 30 μm); chloroform (100 ml)]. Thisgave 50 mg (42% of theory) of4-isopropenyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=406.4, R_(t)=3.58 min.

Step b4-Isopropenyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to50 mg (0.12 mmol) of4-isopropenyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.The mixture was allowed to stand at room temperature for one hour, thetrifluoroacetic acid was then distilled off and the residue was adjustedto pH 7 using sodium bicarbonate solution. The aqueous phase wasextracted three times with in each case 20 ml of dichloromethane. Thecombined organic phases were dried over sodium sulphate and thenconcentrated to dryness. The residue was chromatographed [silica gel 60(12 g, 30 μm); chloroform/methanol 95:5 (100 ml)]. This gave 30 mg (76%of theory) of4-isopropenyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 53-55° C. ¹H NMR (400 MHz, CDCl₃, δ ppm): 2.17(3H), 3.70-3.73 (4H), 3.89-3.92 (4H), 5.12 (1H), 5.46 (1H), 7.02 (1H),7.28 (1H), 7.53 (1H), 7.68 (1H), 8.39 (1H). LC-MS (method 1): m/z:[M+H]⁺=322.3, R_(t)=2.85 min.

Example 112-(morpholin-4-yl)-4-phenyl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine Stepa2-(morpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 74 mg (0.09 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 391 mg (1.2 mmol) of caesiumcarbonate were added to a suspension of 154 mg (0.3 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 245 mg (1.2 mmol) of phenylboronic acidpinacol ester in 6.0 ml of absolute dioxane. The reaction mixture wasstirred at 90° C. for 2 h. The mixture was chromatographed directlywithout work-up [silica gel 60 (12 g, 30 μm); ethyl acetate (100 ml)].This gave 47 mg (36% of theory) of2-(morpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=442.3, R_(t)=3.81 min.

Step b2-(morpholin-4-yl)-4-phenyl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to47 mg (0.11 mmol) of2-(morpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 10 min, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed on a rotary evaporator and the residuethat remained was adjusted to pH 7 using sodium bicarbonate solution.The aqueous phase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. 5 ml of methanol were addedto the residue. The resulting precipitated solid was filtered off usinga frit and then dried. This gave 30 mg (75% of theory) of2-(morpholin-4-yl)-4-phenyl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine as ayellow solid. m.p. 89-91° C. ¹H NMR (400 MHz, CDCl₃, δ ppm): 3.74-3.76(4H), 3.91-3.93 (4H), 7.14 (1H), 7.31 (1H), 7.41 (1H), 7.45-7.47 (2H),7.50-7.55 (3H), 7.70 (1H), 8.35 (1H). LC-MS (method 1): m/z:[M+H]⁺=358.3, R_(t)=3.16 min.

Example 124-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[4-(ethylsulfanyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 24 mg (0.029 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I) was added toa mixture of 150 mg (0.29 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 106 mg (0.58 mmol)[4-(ethylsulfanyl)phenyl]boronic acid in 2.1 ml dioxane and 381 mg (1.17mmol) caesium carbonate. The mixture was stirred at 110° C. for 10minutes. After cooling, the reaction mixture was diluted with ethylacetate and an aqueous solution of sodium chloride. The mixture wasextracted with ethyl acetate (2×) and the combined organic phases werefiltered using a Whatman filter. The organic phase was concentrated andresidue was purified by column chromatography (DCM/ethanol 0%-30%) togive 150 mg (0.03 mmol) of the desired product, containing slightimpurities, that was used without further purifications.

Step bN-[ethyl(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)-λ⁴-sulfanylidene]-2,2,2-trifluoroacetamide

Under an atmosphere of argon, a solution of 49 mg (0.43 mmol)2,2,2-trifluoroacetamide in 0.16 ml THF was added dropwise to a solutionof 27 mg (0.29 mmol) sodium tert.-butoxide in 0.23 ml THF, so that thetemperature of the mixture remained below 10° C. Subsequently, a freshlyprepared solution of 53 mg (0.19 mmol) 1,3-dibromo-5,5-dimethylhydantoinin 0.23 mL THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. Then the mixture wasstirred for 10 minutes at 10° C. Finally, a solution of 145 mg (0.29mmol)4-[4-(ethylsulfanyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.23 ml THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. The mixture was stirredfor 90 minutes at 10° C. and then at room temperature overnight. Thebatch was diluted with 0.6 ml of toluene under cooling and an aqueoussolution of 36 mg (0.29 mmol) sodium sulfite in 1.1 mL water was addedso that the temperature of the mixture remained below 15° C. The batchwas extracted three times with ethyl acetate. The combined organicphases were washed with an aqueous solution of sodium chloride, filteredusing a Whatman filter and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate) to give 33 mg of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ[ppm]=1.42 (3H), 1.61 (5H),2.12 (2H), 2.59 (1H), 3.39 (2H), 3.48 (1H), 3.79 (6H), 3.98 (1H), 6.10(1H), 7.00 (1H), 7.08 (1H), 7.37 (1H), 7.75 (3H), 7.97 (2H), 8.43 (1H).

Step c4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

33 mg (0.054mmol)N-[ethyl(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)-λ⁴-sulfanylidene]-2,2,2-trifluoroacetamidewas dissolved in 1.05 ml methanol. To this solution 0.37 ml water wasadded. The pH was adjusted to 10.5 by addition of an aqueous solution ofpotassium hydroxide (25%). 28 mg (0.046 mmol) Oxone® was added and themixture was stirred at room temperature for 4 hours. Additional 28 mg(0.046 mmol) Oxone® was added. The pH was adjusted to 10.5 by additionof an aqueous solution of potassium hydroxide (25%). The batch wasstirred at room temperature for 90 minutes. The pH was adjusted to 10.5by addition of an aqueous solution of potassium hydroxide (25%) and thebatch was stirred at room temperature for 4 days. The batch was filteredand the filtrate was adjusted to pH 6-7 by the addition of 1N aqueoushydrogen chloride solution. The mixture was diluted with aqueous sodiumchloride solution and extracted with DCM (2×). The combined organicphases were washed with an aqueous solution of sodium sulfite (10%),filtered using a Whatman filter, and concentrated to give 25 mg crudeproduct that was used without further purification.

Step d4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.05 ml (0.11 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 25 mg crude4-[4-(S-ethylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.22 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: basic conditions) to give 5 mg (0.01 mmol) of the desiredproduct. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=1.15 (3H), 3.22 (2H), 3.81(8H), 4.34 (1H), 7.36 (1H), 7.44 (1H), 7.56 (1H), 7.65 (1H), 7.81 (2H),8.08 (2H), 8.35 (1H), 13.43 (1H).

Example 133-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideStep a3-[(-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

Under argon, 48 mg (0.06 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 761 mg (2.34 mmol) of caesiumcarbonate were added to a suspension of 300 mg (0.58 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in7.5 ml of absolute dioxane. The reaction mixture was stirred at 100° C.for 3 h. The mixture was chromatographed directly without work-up[silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)]. This gave 270 mg(78% of theory) of3-[(-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=591.3, R_(t)=3.42 min.

Step b3-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

260 mg (0.44 mmol) of3-[(-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere dissolved in 10 ml of ethanol, and 5 ml of (10 mmol) of 2Nhydrochloric acid were added. After 1 h, LCMS showed complete removal ofthe protective group. Ethanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. The residuewas chromatographed [silica gel 60 (25 g, 30 μm); ethyl acetate (100ml)]. This gave 160 mg (72% of theory) of3-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideas a yellow solid. m.p. 115-117° C. ¹H NMR (400 MHz, DMSO-d₆):δ[ppm]=1.09-1.13 (3H), 3.57 (3H), 3.81 (8H), 3.98-4.00 (2H), 7.34-7.35(1H), 7.42 (1H), 7.56 (1H), 7.65 (1H), 7.91-7.96 (1H), 7.98-7.99 (1H),8.10-8.33 (2H), 8.33-8.34 (1H), 13.40 (1H). LC-MS (method 1): m/z:[M+H]⁺=507.3, R_(t)=2.93 min.

Example 144-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 12 mg (0.015 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added toa mixture of 75 mg (0.15 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 65 mg (0.29 mmol)1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinein 1.1 ml dioxane and 190 mg (0.58 mmol) caesium carbonate. The mixturewas stirred at 110° C. for 150 minutes. After cooling, the reactionmixture was diluted with ethyl acetate and an aqueous solution of sodiumchloride. The mixture was extracted with ethyl acetate (2×) and thecombined organic phases were filtered using a Whatman filter. Theorganic phase was concentrated and the crude product (142 mg) was usedwithout further purification.

Step b4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.36 ml (0.71 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 142 mg crude4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.4 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: basic conditions) to give 22 mg (0.06 mmol) of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ[ppm]=2.51 (3H), 2.59 (2H),2.78 (2H), 3.23 (2H), 3.76 (4H), 3.96 (4H), 5.89 (1H), 7.07 (1H), 7.31(1H), 7.57 (1H), 7.73 (1H), 8.43 (1H), 12.99 (1H).

Example 154-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 24 mg (0.03 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 381 mg (1.17 mmol) of caesiumcarbonate were added to a suspension of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 165 mg (0.58 mmol) of2-(3-methanesulphonylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in5.0 ml of absolute dioxane. The reaction mixture was stirred at 90° C.for 16 h. The mixture was chromatographed directly without work-up[silica gel 60 (25 g 30 μm); chloroform/methanol 95:5 (100 ml)]. Thisgave 80 mg (53% of theory) of4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=520.3, R_(t)=3.33 min.

Step b4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to80 mg (0.15 mmol) of4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After one hour of stirring at room temperature, the trifluoroacetic acidwas distilled off and the residue was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. The residuewas chromatographed [silica gel 60 (12 g, 30 μm); chloroform/methanol90:10 (100 ml)]. This gave 30 mg (45% of theory) of4-(3-methanesulphonylphenyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 255-257° C. ¹H NMR (400 MHz, DMSO, δ ppm): 3.30(3H), 3.81 (8H), 7.36 (1H), 7.43 (1H), 7.56 (1H), 7.64 (1H), 7.86-7.95(2H), 8.10-8.13 (2H), 8.35 (1H), 13.41 (1H). LC-MS (method 1): m/z:[M+H]⁺=436.2, R_(t)=2.80 min.

Example 164-[5-methyl-6-(methylsulfonyl)pyrdin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[5-methyl-6-(methylsulfonyl)pyrdin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 16 mg (0.019 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 100 mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 116 mg (0.39 mmol)3-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinein 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixturewas stirred at 130° C. for 10 minutes in a microwave oven. Aftercooling, the reaction mixture was diluted with DCM and filtered using aWhatman filter. The organic phase was concentrated and the crude product(119 mg) was used without further purification.

Step b4-[5-methyl-6-(methylsulfonyl)pyrdin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.22 ml (0.45 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 119 mg crude4-[5-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.0 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preperative HPLC(Autopurifier: basic conditions) to give 7 mg (0.016 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=2.73 (3H), 3.48 (3H),3.81 (8H), 7.41 (2H), 7.66 (2H), 8.22 (1H), 8.35 (1H), 8.73 (1H), 13.44(1H).

Example 172-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-naphthyridineStep a2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-naphthyridine

Under argon, 12 mg (0.015 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(I) was added toa mixture of 75 mg (0.15 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 71 mg (0.29 mmol)4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride (1:1) in 1.1 ml dioxane and 285 mg (0.88 mmol) caesiumcarbonate. The mixture was stirred at 110° C. for 4 hours. Aftercooling, the reaction mixture was diluted with ethyl acetate and anaqueous solution of sodium chloride. The mixture was extracted withethyl acetate (2×) and the combined organic phases were filtered using aWhatman filter. The organic phase was concentrated and residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 16mg (0.04 mmol) of the desired product. ¹H-NMR (400 MHz, CDCl₃):δ[ppm]=1.76 (5H), 2.09 (2H), 2.52 (3H), 3.23 (2H), 3.47 (1H), 3.69 (5H),3.83 (4H), 3.98 (1H), 5.93 (1H), 6.03 (1H), 6.95 (1H), 6.97 (1H), 7.64(1H), 7.72 (1H), 8.43 (1H).

Step b2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-naphthyridine

0.04 ml (0.08 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 16 mg (0.036 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-naphthyridinein 0.17 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated to give 11 mg (0.030 mmol) of the desired product.¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=2.32 (2H), 2.98 (2H), 3.42 (2H), 3.67(1H), 3.76 (8H), 5.90 (1H), 7.29 (1H), 7.36 (1H), 7.63 (1H), 7.67 (1H),8.35 (1H), 13.30 (1H).

Example 184-cyclopropyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-cyclopropyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 80 mg (0.1 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 635 mg (2.0 mmol) of caesiumcarbonate were added to a suspension of 250 mg (0.49 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 84 mg (0.97 mmol) of2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 5 ml ofabsolute dioxane. The reaction mixture was stirred at 110° C. for 4 h.The mixture was chromatographed directly without work-up [silica gel 60(40 g, 30 μm); chloroform/methanol (1:1, 100 ml)]. This gave 150 mg (76%of theory) of4-cyclopropyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=406.3, R_(t)=3.53 min.

Step b4-cyclopropyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to150 mg (0.37 mmol) of4-cyclopropyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 1 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was distilled off under reduced pressure and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. 5 ml of methanol wereadded to the residue, resulting in the precipitation of a solid. Thelatter was filtered off and dried. This gave 30 mg (25% of theory) of4-cyclopropyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 211-214° C. ¹H NMR (400 MHz, DMSO):δ[ppm]=0.92-0.96 (2H), 1.10-1.14 (2H), 2.42-2.44 (1H), 3.72-3.73 (4H),3.77-3.78 (4H), 7.08 (1H), 7.36 (1H), 7.61 (1H), 7.99-8.00 (1H),8.40-8.42 (1H), 13.34 (1H). LC-MS (method 1): m/z: [M+H]⁺=322.3,R_(t)=2.68 min.

Example 193-[(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximide

120 mg (0.24 mmol) of3-[(2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere suspended in 8 ml of sodium methoxide (33%), and the mixture wasstirred at 60° C. for 30 min. For work-up, 20 ml of water were added andthe mixture was then extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and concentrated. This gave 100 mg (97% of theory)3-[(2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideas a yellow solid. m.p. 227-229° C. ¹H NMR (400 MHz, CDCl₃-d₆):δ[ppm]=3.22 (3H), 3.79-3.81 (4H), 3.94-3.96 (4H), 7.20 (1H), 7.30-7.32(1H), 7.35-7.36 (1H), 7.73-7.76 (3H), 8.18-8.20 (2H), 8.40-8.41 (1H).LC-MS (method 1): m/z: [M+H]⁺=435.3, R_(t)=2.63 min.

Example 204-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride Step a4-methyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 91 mg (0.11 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 241 mg (0.74 mmol) of caesiumcarbonate were added to a suspension of 190 mg (0.37 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 44 mg (0.74 mmol) of methylboronic acidin 2.5 ml of absolute dioxane. The reaction mixture was stirred at 90°C. for 2 h. The mixture was chromatographed directly without work-up[silica gel 60 (40 g, 30 μm); chloroform/methanol (95:5, 100 ml)]. Thisgave 120 mg (86% of theory) of4-methyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=380.3, R_(t)=3.23 min.

Step b4-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 2 ml of (26 mmol) of trifluoroacetic acid were addedto 120 mg (0.32 mmol) of4-methyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 1 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was distilled off under reduced pressure and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (12 g, 30 μm); chloroform (100 ml)]. Thisgave 45 mg (48% of theory) of4-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine as ayellow solid. After brief exposure to air, this solid becamediscoloured. For this reason, the compound was converted into thecorresponding hydrochloride. LC-MS (method 1): m/z: [M+H]⁺=296.3,R_(t)=2.53 min.

Step c4-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride

45 mg (0.15 mmol) of4-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine weredissolved in 4.0 ml of 2-butanol, and 58 μl (0.46 mmol) oftrimethylchlorosilane were added. The reaction solution was stirred atroom temperature for 1 h. The precipitated solid was filtered off andthen dried. This gave 45 mg (89% of theory) of4-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride as a yellow solid. m.p. 164-166° C. ¹H NMR (400 MHz, DMSO,δ ppm): 2.69 (3H), 3.81-3.86 (8H), 7.55 (1H), 7.82 (1H), 8.11-8.14 (2H),8.38 (1H). LC-MS (method 1): m/z: [M+H]⁺=296.3, R_(t)=2.51 min.

Example 214-[2-(methylsulfonyl)-1,3-thiazol-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-(methylsulfonyl)-1,3-triazol-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 16 mg (0.019 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 100 mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 113 mg (0.39 mmol)2-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazolein 1.4 ml dioxane and 254 mg (0.78 mmol) caesium carbonate. The mixturewas stirred at 110° C. for 2 hours. After cooling, the reaction mixturewas diluted with ethyl acetate and an aqueous solution of sodiumchloride. The mixture was extracted with ethyl acetate (2×) and thecombined organic phases were filtered using a Whatman filter. Theorganic phase was concentrated and the crude product (263 mg) was usedwithout further purification.

Step b4-([2-(methylsulfonyl)-1,3-thiazol-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.58 ml (1.15 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 263 mg crude4-[2-(methylsulfonyl)-1,3-thiazol-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 2.3 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: acidic conditions) to give 3 mg (0.007 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.61 (3H), 3.82 (8H),7.41 (1H), 7.66 (1H), 7.82 (1H), 7.95 (1H), 8.41 (1H), 8.82 (1H), 13.42(1H).

Example 224-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin-2(1H)-oneStep a4-(2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate (320 mg, 0.21 mmol),(2-methoxypyridin-4-yl)boronic acid (94 mg, 0.62 mmol),Bis(triphenylphosphin)palladium(II)chlorid (14 mg, 0,021 mmol),Caesiumcarbonate (235 mg, 0.72 mmol) in Dioxane (4 ml) were heated in asealed tube in the Microwave at 100. C for 30 minutes. A solution ofconc. HCl (10 ml) was added and the reaction was stirred at ambienttemperature for 16 hours and at 50° C. for another 2 hours. The reactionmixture was filtered through a plug of Celite (1 cm). The Celite waswashed with ethyl acetate (50 ml) and methanol (20 ml). The filtrate wasdried over Na₂SO₄, the solvent was removed under reduced pressure. Thetitle compound was obtained as crude product and used without furtherpurification in the next step.

Step b4-([2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin-2(1H)-one

Crude4-(2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(1.882 g, purity ca. 10%) was added to a solution of concentrated HBr inacetic acid (2 ml) and acetic acid (15 ml) and stirred at 100° C. for 2hours. The reaction was cooled to ambient temperature, dichloromethane(30 ml) and a saturated aqueous solution of NaHCO₃ (50 ml) was added.The layers were separated and the aqueous phase was extracted withdichloromethane (2×10 ml). The combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct (188 mg) was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 1% yield (1.6 mg).¹H-NMR (400 MHz, DMSO): δ[ppm]=3.80 (8H), 6.33 (1H), 6.50 (1H),7.41-7.66 (5H), 8.36 (1H), 11.89 (1H), 13.44 (1H).

Example 235-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin-2(1H)-oneStep a4-(6-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate (605 mg, 0.39 mmol),(6-methoxypyridin-3-yl)boronic acid (178 mg, 1.17 mmol),Bis(triphenylphosphin)palladium(II)chlorid (27 mg, 0,039 mmol),Caesiumcarbonate (443 mg, 1.36 mmol) in Dioxane (4 ml) were heated in asealed tube in the Microwave at 100′ C for 30 minutes. A solution ofconc. HCl (10 ml) was added and the reaction was stirred at ambienttemperature for 16 hours and at 50° C. for another 2 hours. The reactionmixture was filtered through a plug of Celite (1 cm). The Celite waswashed with ethyl acetate (50 ml) and methanol (20 ml). The filtrate wasdried over Na₂SO₄, the solvent was removed under reduced pressure. Thetitle compound was obtained as crude product and used without furtherpurification in the next step.

Step b5-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin-2(1H)-one

Crude4-(6-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(1.344 g, purity ca. 10%) was added to a solution of concentrated HBr inacetic acid (2 ml) and acetic acid (15 ml) and stirred at 100° C. for 2hours. The reaction was cooled to ambient temperature, dichloromethane(30 ml) and a saturated aqueous solution of NaHCO₃ (50 ml) was added.The layers were separated and the aqueous phase was extracted withdichloromethane (2×10 ml). The combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct (188 mg) was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 2% yield (2.3 mg). H-NMR(400 MHz, DMSO): δ[ppm]=3.79 (8H), 6.51 (1H), 7.40 (1H), 7.48 (1H), 7.51(1H), 7.64-7.70 (3H), 8.36 (1H), 12.10 (1H), 13.40 (1H).

Example 244-([2-fluoro-4-(methylsulfonyl)phenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-4-(methylsulfanyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 24 mg (0.029 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 150 mg (0.29 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 108 mg (0.58 mmol)[2-fluoro-4-(methylsulfanyl)phenyl]boronic acid in 2.1 ml dioxane and381 mg (1.17 mmol) caesium carbonate. The mixture was stirred at 110° C.for 2 hours. After cooling, the reaction mixture was diluted with ethylacetate and washed with aqueous sodium chloride solution. The organicphase was filtered using a Whatman filter and concentrated. The residuewas purified by column chromatography (hexane/ethyl acetate 20%-70%) togive 126 mg (0.25 mmol) of the desired product.

Step b4-([2-fluoro-4-(methylsulfonyl)phenyl)-2-(morpholin-4-yl)-8-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 2 mg (0.006 mmol) tetrapropylammonium perruthenate (TPAP)and 14 mg (0.127 mmol)N-methylmorpholine-N-oxide (NMO) were added to asolution of 64 mg (0.127 mmol)4-[2-fluoro-4-(methylsulfanyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.4 mL DCM and 1.4 mL acetonitrile at 0° C. The mixture was stirredfor 4 hours at 0° C. Additional 14 mg (0.127mmol)N-methylmorpholine-N-oxide (NMO) was added and the mixture wasstirred at 0° C. for 7 hours and then for 40 minutes at 10° C. Finally,the batch was concentrated to give 81 mg crude product that was usedwithout further purification.

Step c4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.17 ml (0.35 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 81 mg crude4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.7 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by preperative HPLC(Autopurifier: acidic conditions) to give 18 mg (0.04 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO): δ[ppm]=3.40 (3H), 3.80 (8H),7.20 (1H), 7.44 (1H), 7.70 (2H), 7.88 (1H), 8.00 (1H), 8.06 (1H), 8.33(1H), 13.55 (1H).

Example 252-(morpholin-4-yl)-4-(4-[S-(propan-2-yl)sulfonimidoyl]phenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-(morpholin-4-yl)-4-[4-(propan-2-ylsulfanyl)phenyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 16 mg (0.019 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was added toa mixture of 100 mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 76 mg (0.39 mmol)[4-(propan-2-ylsulfanyl)phenyl]boronic acid in 1.4 ml dioxane and 253 mg(0.78 mmol) caesium carbonate. The mixture was stirred at 110° C. for 2hours. After cooling, the reaction mixture was diluted with ethylacetate and an aqueous solution of sodium chloride. The mixture wasextracted with ethyl acetate (2×) and the combined organic phases werefiltered using a Whatman filter. The organic phase was concentrated andresidue was purified by column chromatography (hexane/ethyl acetate20%-80%) to give 74 mg (0.14 mmol) of the desired product, containingslight impurities, that was used without further purifications.

Step b2,2,2-trifluoro-N-[(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)(propan-2-yl)-λ⁴-sulfanylidene]acetamide

Under an atmosphere of argon, a solution of 39 mg (0.35 mmol)2,2,2-trifluoroacetamide in 0.13 ml THF was added dropwise to a solutionof 22 mg (0.23 mmol) sodium tert.-butoxide in 0.19 ml THF, so that thetemperature of the mixture remained below 10° C. Subsequently, a freshlyprepared solution of 43 mg (0.15 mmol) 1,3-dibromo-5,5-dimethylhydantoinin 0.19 ml THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. Then the mixture wasstirred for 10 minutes at 10° C. Finally, a solution of 120 mg (0.23mmol)2-(morpholin-4-yl)-4-[4-(propan-2-ylsulfanyl)phenyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.23 ml THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. The mixture was stirredfor 80 minutes at 10° C. and then at room temperature overnight. Thebatch was diluted with 0.5 ml toluene under cooling and an aqueoussolution of 29 mg (0.23 mmol) sodium sulfite in 0.9 ml water was addedso that the temperature of the mixture remained below 10° C. The batchwas extracted three times with ethyl acetate. The combined organicphases were washed with an aqueous solution of sodium chloride, filteredusing a Whatman filter and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate) to give 28 mg of thedesired product containing slight impurities.

Step c4-[4-(S-isopropylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

28 mg (0.035 mmol)2,2,2-trifluoro-N-[(4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)(propan-2-yl)-λ⁴-sulfanylidene]acetamidewas dissolved in 0.87 ml methanol. To this solution 0.31 ml water wasadded. The pH was adjusted to 10.5 by addition of an aqueous solution ofpotassium hydroxide (25%). 23 mg (0.038 mmol) Oxone® was added and themixture was stirred at room temperature for 4 hours. Additional amount23 mg (0.038 mmol) Oxone® was added. The pH was adjusted to 10.5 byaddition of an aqueous solution of potassium hydroxide (25%). The batchwas stirred at room temperature for 90 minutes. The pH was adjusted to10.5 by addition of an aqueous solution of potassium hydroxide (25%) andthe batch was stirred at room temperature for 4 days. The batch wasfiltered and the filtrate was adjusted to pH 6-7 by the addition of 1Naqueous hydrogen chloride solution. The mixture was diluted with aqueoussodium chloride solution and extracted with DCM (2×). The combinedorganic phases were washed with an aqueous solution of sodium sulfite(10%), filtered using a Whatman filter, and concentrated to give 21 mgcrude product that was used without further purification.

Step d2-(morpholin-4-yl)-4-(4-[S-(propan-2-yl)sulfonimidoyl]phenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.04 ml (0.11 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 21 mg crude2-(morpholin-4-yl)-4-{4-[S-(propan-2-yl)sulfonimidoyl]phenyl}-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.18 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desiredproduct. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=1.22 (6H), 3.35 (1H), 3.81(8H), 4.30 (1H), 7.36 (1H), 7.44 (1H), 7.57 (1H), 7.65 (1H), 7.82 (2H),8.05 (2H), 8.35 (1H), 13.43 (1H).

Example 264-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 120 mg (227 μmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate, 76 mg (0.38 mmol) of4-(methanesulphonyl)phenylboronic acid, 18 mg (22.7 μmol) of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)×dichloromethaneand 296 mg (0.91 mmol) of caesium carbonate were weighed out anddissolved in 1.5 ml of absolute 1,4-dioxane. The mixture was degassedthree times and stirred at 90° C. for 2 h. The course of the reactionwas monitored by LC/MS. Since conversion was incomplete, another 52 mgof 4-(methanesulphonyl)phenylboronic acid, 18 mg of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)×dichloromethaneand 296 mg of caesium carbonate were added to the reaction solution andthe mixture was stirred at 90° C. for 20 h. Under reduced pressure, themixture was concentrated to dryness. The residue was chromatographed[silica gel 60 (40 g, 50 μm); dichloromethane/methanol 98:2 to 95:5]. 79mg (65% of theory) of4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere obtained as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ[ppm]=1.34 (3H), 1.48-1.74 (3H), 2.08-2.11(2H), 2.56 (1H), 3.19 (3H), 3.34 (1H), 3.46 (1H), 3.59 (1H), 3.71-3.84(3H), 3.94 (1H), 4.02-4.24 (2H), 4.44 (1H), 6.08 (1H), 6.98 (1H), 7.01(1H), 7.69-7.72 (3H), 8.14 (2H), 8.40 (1H). LC-MS (method 1): R_(t)=3.46min; MS (ESI/APCIpos) m/z=534.3 [M+H]⁺.

Step b4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine

79 mg (0.15 mmol) of4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 5 ml of methanol, 1 ml of 2N hydrochloric acid (2mmol) was added and the mixture was stirred at room temperature for 1 h.After 1 h, LC/MS showed complete removal of the protective group. Themethanol was removed under reduced pressure and the residue was adjustedto pH=7 using saturated sodium bicarbonate solution. The aqueous phasewas extracted five times with in each case 10 ml of dichloromethane. Thecombined organic phases were dried over sodium sulphate and concentratedto dryness under reduced pressure. The residue was washed twice with ineach case 4 ml of methanol, filtered off and dried. This gave 44 mg (66%of theory) of4-(4-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ[ppm]=1.31 (3H), 3.33(3H), 3.32-3.40 (1H), 3.57 (1H), 3.72 (1H), 3.83 (1H), 4.05 (1H), 4.24(1H), 4.66 (1H), 7.35 (1H), 7.43 (1H), 7.50 (1H), 7.61 (1H), 7.87 (2H),8.13 (2H), 8.33 (1H), 13.4 (1H). LC-MS (method 1): R_(t)=2.88 min; MS(ESI/APCIpos) m/z=450.2 [M+H]⁺.

Example 272-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineStep a2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 120 mg (227 μmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate, 46 mg (0.38 mmol) of benzeneboronic acid, 18mg (0.0227 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)×dichloromethaneand 296 mg (0.91 mmol) of caesium carbonate were weighed out anddissolved in 1.5 ml of absolute 1,4-dioxane. The mixture was degassedthree times and stirred at 90° C. for 1 h. The course of the reactionwas monitored by LC/MS. The mixture was concentrated to dryness underreduced pressure. The residue was chromatographed [silica gel 60 (40 &50 μm); dichloromethane/methanol 98:2 to 95:5]. This gave 90 mg (87% oftheory) of2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ[ppm]=1.33 (3H), 1.48-1.51(1H), 1.62-1.77 (2H), 2.07-2.10 (2H), 2.56 (1H), 3.32 (1H), 3.46 (1H),3.58 (1H), 3.69-3.83 (2H), 3.94-3.98 (1H), 4.03-4.52 (3H), 6.05 (1H),6.97 (1H), 7.02 (1H), 7.47-7.56 (6H), 7.71 (1H), 8.38 (1H). LC-MS(method 1): R_(t)=3.89 min; MS (ESI/APCIpos) m/z=456.3 [M+H]⁺.

Step b2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine

90 mg (0.20 m mol) of2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 5 ml of methanol, 1 ml of 2N hydrochloric acid (2mmol) was added and the mixture was stirred at room temperature for 1 h.After 1 h, LC/MS showed complete removal of the protective group. Themethanol was removed under reduced pressure and the residue was adjustedto pH=7 using saturated sodium bicarbonate solution. The aqueous phasewas extracted five times with in each case 10 ml of dichloromethane. Thecombined organic phases were dried over sodium sulphate and then, underreduced pressure, concentrated to dryness. The residue waschromatographed twice [silica gel 60 (25 g, 30 μm);dichloromethane/methanol 96:4]. This gave 52 mg (71% of theory) of2-((R)-3-methylmorpholin-4-yl)-4-phenyl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineas an orange solid. ¹H NMR (400 MHz, CDCl₃): δ[ppm]=1.46 (3H), 3.57(1H), 3.72 (1H), 3.84-3.94 (2H), 4.04 (1H), 4.17 (1H), 4.46 (1H), 7.14(1H), 7.32 (1H), 7.43 (1H), 7.47-7.58 (5H), 7.72 (1H), 8.38 (1H). ¹³CNMR (101 MHz, CDCl₃): δ[ppm]=13.6, 40.6, 48.6, 66.7, 71.1, 106.3, 113.5,117.8, 126.9, 120.8, 129.0, 129.2, 137.2, 140.1, 140.4, 140.5, 143.0144.7, 149.9, 156.8. LC-MS (method 1): R_(t)=3.32 min; MS (ESI/APCIpos)m/z=372.2 [M+H]⁺.

Example 284-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 120 mg (227 μmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yltrifluoromethanesulphonate, 76 mg (0.38 mmol) of3-(methanesulphonyl)phenylboronic acid, 18 mg (22.7 μmol) of[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)×dichloromethaneand 296 mg (0.91 mmol) of caesium carbonate were weighed out anddissolved in 1.5 ml of absolute 1,4-dioxane. The mixture was degassedthree times and stirred at 90° C. for 90 min. The course of the reactionwas monitored by LC/MS. Under reduced pressure, the mixture wasconcentrated to dryness. The residue was chromatographed [silica gel 60(25 g 30 μm); dichloromethane/methanol 98:2]. This gave 72 mg (60% oftheory) of4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ[ppm]=1.32-1.37 (3H),1.49-1.69 (1H), 1.69 (2H), 2.09 (2H), 2.55 (1H), 2.68 (3H), 3.27-3.39(1H), 3.47 (1H), 3.59 (1H); 3.77 (2H), 3.94-4.48 (4H), 6.10 (1H),6.93-6.95 (1H), 7.02-7.08 (1H), 7.20-7.25 (1H), 7.42 (1H), 7.71-7.79(3H), 8.32-8.35 (2H). LC-MS (method 1): R_(t)=3.43 min; MS (ESI/APCIpos)m/z=534.3 [M+H]⁺.

Step b4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine

72 mg (0.13 mmol) of4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 5 ml of methanol, 1 ml of 2N hydrochloric acid (2mmol) was added and the mixture was stirred at room temperature for 1 h.After 1 h, LC/MS showed complete removal of the protective group. Themethanol was removed under reduced pressure and the residue was adjustedto pH=7 using saturated sodium bicarbonate solution. The aqueous phasewas extracted five times with in each case 10 ml of dichloromethane. Thecombined organic phases were dried over sodium sulphate and then, underreduced pressure, concentrated to dryness. The residue waschromatographed twice [silica gel 60 (25 g, 30 μm);dichloromethane/methanol 96:4]. This gave 37 mg (61% of theory) of4-(3-methanesulphonylphenyl)-2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineas an orange solid. ¹H NMR (400 MHz, CDCl₃): δ[ppm]=1.46 (3H), 2.66(3H), 3.58 (1H), 3.72 (1H), 3.83-3.92 (2H), 4.04-4.20 (2H), 4.39 (1H),6.91 (1H), 7.33-7.37 (2H), 7.42 (1H), 7.73-7.80 (3H), 8.33 (2H). LC-MS(method 1): R_(t)=2.80 min; MS (ESI/APCIpos) m/z=450.2 [M+H]⁺.

Example 294-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-([1,7-naphthyridineStep a4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin

Under argon, 82 mg (0.1 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 652 mg (2.0 mmol) of caesiumcarbonate were added to a suspension of 264 mg (0.5 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 86 mg (1 mmol) of2-cyclopropyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 5 ml ofabsolute dioxane. The reaction mixture was stirred at 110° C. for 4 h.Without work-up, the mixture was chromatographed directly [Puri-Flash,silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)]. This gave 100 mg(48% of theory) of4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. ¹³C NMR (101 MHz, CDCl₃-d₆): δ[ppm]=6.9, 7.0, 12.5,13.5, 22.8, 25.0, 30.0, 39.4, 39.7, 47.1, 47.7, 66.9, 67.0, 67.6, 71.1,84.8, 108.8, 110.2, 116.6, 128.0, 128.1, 138.5, 138.6, 139.0, 139.1,140.3, 141.7, 148.2, 149.6, 156.6, 156.7.

Step b4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]-naphthyridine

100 mg (0.24 mmol) of4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 5 ml of methanol, and 1 ml (2 mmol) of 2N hydrochloricacid was added. After 1 h, LCMS showed complete removal of theprotective group. The methanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. The residuewas chromatographed [Puri-Flash, silica gel 60 (12 g, 30 μm); ethylacetate (100 ml)]. This gave 70 mg (88% of theory) of4-cyclopropyl-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 74-76° C. ¹H NMR (400 MHz, CDCl₃):δ[ppm]=0.78-0.82 (2H), 1.14-1.17 (2H), 1.38-1.40 (3H), 2.24-2.28 (1H),3.46-3.52 (1H), 3.64-3.71 (1H), 3.80-3.96 (3H), 4.11-4.15 (1H),4.37-4.39 (1H), 6.86 (1H), 7.26-7.26 (1H), 7.68-7.69 (1H), 7.81-7.83(1H), 8.44-8.45 (1H).

Example 304-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideStep a4-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

Under argon, 48 mg (0.06 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 761 mg (2.34 mmol) of caesiumcarbonate were added to a suspension of 308 mg (0.58 mmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in7.5 ml of absolute dioxane. The reaction mixture was stirred at 90° C.for 2 h. The mixture was chromatographed directly without work-up[silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)]. This gave 245 mg(69% of theory) of4-[(2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximideas a yellow foam. LC-MS (method 1): m/z: [M+H]⁺=605.3, R_(t)=3.52 min.

Step b4-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-(S)-methylsulphoximide

240 mg (0.40 mmol) of4-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere dissolved in 10 ml of ethanol, and 4 ml of (8 mmol) of 2Nhydrochloric acid were added. After 1 h, LCMS showed complete removal ofthe protective group. Ethanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. This gave200 mg (97% of theory) of2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carbonitrileas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=521.3, R_(t)=3.00 min.

Step c4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximide

170 mg (0.33 mmol) of4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximidewere suspended in 5 ml of sodium methoxide (33%), and the mixture wasstirred at 60° C. for 30 min. For work-up, 20 ml of water were added andthe mixture was then extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and concentrated. The solid formed was triturated with 5 ml ofmethanol, filtered off and dried. This gave 88 mg (57% of theory) of4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideas a yellow solid. m.p. 233-236° C. ¹H NMR (400 MHz, DMSO-d₆):δ[ppm]=1.30-1.32 (3H), 3.17 (3H), 3.54 (1H), 3.55-3.57 (1H), 3.70-3.73(1H), 3.81-3.84 (1H), 4.22-4.25 (1H), 4.35 (1H), 7.35-7.36 (1H), 7.42(1H), 7.48 (1H), 7.65 (1H), 7.80-7.82 (2H), 8.12-8.14 (2H), 8.33-8.34(1H), 13.40 (1H). LC-MS (method 1): m/z: [M+H]⁺=449.3, R_(t)=2.69 min.

Example 313-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideStep a3-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

Under argon, 48 mg (0.06 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 761 mg (2.34 mmol) of caesiumcarbonate were added to a suspension of 308 mg (0.58 mmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 413 mg (1.17 mmol) of pinacol ester in7.5 ml of absolute dioxane. The reaction mixture was stirred at 90° C.for 2 h. The mixture was chromatographed directly without work-up[silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)]. This gave 289 mg(82% of theory) of3-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxy-carbonyl-S-methylsulphoximideas a yellow oil. LC-MS (method 1): m/z: [M+H]*=605.3, R_(t)=3.56 min.

Step b4-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide

280 mg (0.46 mmol) of3-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere dissolved in 10 ml of ethanol, and 4 ml of (10 mmol) of 2Nhydrochloric acid were added. After 1 h, LCMS showed complete removal ofthe protective group. Ethanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. The residuewas chromatographed [silica gel 60 (25 g, 30 μm); ethyl acetate (100ml)]. This gave 220 mg (91% of theory) of2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carbonitrileas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=521.3, R_(t)=3.04 min.

Step c3-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximide

210 mg (0.40 mmol) of4-[2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximidewere suspended in 5 ml of sodium methoxide (33%), and the mixture wasstirred at 60° C. for 30 min. For work-up, 20 ml of water were added andthe mixture was then extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and concentrated. This gave 165 mg (91% of theory) of3-[2-((R)-3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]phenyl-S-methylsulphoximideas a yellow solid. m.p. 79-81° C. ¹H NMR (400 MHz, DMSO-d₆):δ[ppm]=1.30-1.32 (3H), 3.18 (3H), 3.57-3.58 (1H), 3.71-3.75 (1H),3.82-3.85 (1H), 4.03-4.06 (1H), 4.21-4.24 (1H), 4.34 (1H), 4.67-4.68(1H), 7.35-7.36 (1H), 7.42 (1H), 7.48 (1H), 7.65 (1H), 7.80-7.82 (2H),8.12-8.14 (2H), 8.33-8.34 (1H), 13.40 (1H). LC-MS (method 1): m/z:[M+H]⁺=449.3, R_(t)=2.69 min.

Example 324-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineStep a4-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

A solution of 500 mg (1.25 mmol) of4-chloro-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine,140 mg (1.38 mmol) of sodium methanesulphinate, 45 mg (0.13 mmol) ofcopper(II) trifluoromethanesulphonate and 29 mg (0.25 mmol) of(±)-trans-1,2-diaminocyclohexane in 5 ml of dimethyl sulphoxide wasstirred at 100° C. for 16 h. 20 ml of water were added to the reactionmixture. The resulting precipitated solid was filtered off. The solidwas purified by column chromatography [Puri-Flash, silica gel 60 (40 g30 μm), dichloromethane/methanol 1:1 (300 ml)]. In this manner,4-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewas obtained as a yellow solid in a yield of 300 mg (54% of theory).LC-MS (method 1): m/z: [M+H]⁺=444.3, R_(t)=3.24 min.

Step b4-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

300 mg (0.67 mmol) of4-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 5 ml of methanol, and 1 ml (4 mmol) of 2N hydrochloricacid was added. After 1 h, LCMS showed complete removal of theprotective group. Methanol was distilled off under reduced pressure andthe residue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The solid residue wastriturated with 5 ml of methanol, filtered off and dried. This gave 146mg (60% of theory) of4-methanesulphonyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. m.p. 271-273° C. ¹H NMR (400 MHz, DMSO, δ ppm): 3.48(3H), 3.80 (8H), 7.35 (1H), 7.65 (1H), 7.93 (1H), 8.14-8.16 (1H),8.49-8.50 (1H), 13.43 (1H). LC-MS (method 1): m/z: [M+H]⁺=360.2,R_(t)=2.78 min.

Example 332-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

4-Chloro-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(50 mg, 0.12 mmol, 1 eq.) was solubilised in DMF (4 mL). Methanesulfinicacid sodium salt (25 mg, 0.24 mmol, 2 eq.) and DMAP (1.5 mg, 0.012 mmol,0.1 eq.) were added. The reaction was stirred for 16 h at 120° C. Aftercooling to rt, the reaction mixture was concentrated under reducedpressure and the crude was purified by flash column chromatography(gradient 100% hexane to 100% EtOAc). The desired product was obtainedin 74% yield (46 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.24 (3H),1.39-1.65 (3H), 1.89-2.03 (2H), 2.34-2.43 (1H), 3.20-3.29 (1H),3.41-3.54 (5H), 3.58-3.73 (2H), 3.77 (1H), 3.94-4.01 (1H), 4.12 (1H),4.45-4.56 (1H), 5.97-6.08 (1H), 6.89 (1H), 7.64 (1H), 7.84 (1H), 8.19(1H), 8.54 (1H). LC-MS (Method 3): m/z: [M+H]⁺=458, R_(t)=1.01 min.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

2-[(3R)-3-Methylmorpholin-4-yl]-4-(methylsulfonyl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(38 mg, 0.084 mmol, 1 eq.) was solubilised in CH₂Cl₂ (1.5 mL) and H₂O (1mL). Formic acid was added (1 mL) and the reaction was stirred for 2 hat rt. The mixture was then quenched with sat. NaHCO₃ and the aqueousphase was extracted three times with CH₂Cl₂. The organic phase was dried(silicon filter) and concentrated under reduced pressure. The crudemixture was purified by flash column chromatography (gradient from 100%hex to 100% EtOAc to EtOAc/EtOH: 8/2). The desired compound was obtainedin 85% yield. ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.32 (3H), 3.36-3.46(1H), 3.49 (3H), 3.57 (1H), 3.71 (1H), 3.84 (1H), 4.06 (1H), 4.17 (1H),4.57-4.66 (1H), 7.37 (1H), 7.63-7.66 (1H), 7.88 (1H), 8.14 (1H), 8.49(1H), 13.46 (1H). LC-MS (Method 3): m/z: [M+H]⁺=374, R_(t)=0.81 min.

Example 342-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carbonitrileStep a2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrile

Under argon, 34 mg (0.029 mmol) oftetrakis(triphenylphosphine)palladium(0) were added to a suspension of500 mg (0.97 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 43 mg (0.37 mmol) of zinc cyanide in 5 mlof absolute dimethylformamide. The reaction mixture was stirred at 130°C. for 1 h. 30 ml of sodium bicarbonate solution were added to themixture. The aqueous phase was extracted three times with in each case40 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The residue wastriturated with 10 ml of ethyl acetate, filtered off and then dried.This gave 260 mg (68% of theory) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrileas a colourless solid. LC-MS (method 1): m/z: [M+H]⁺=391.3, R_(t)=3.44min.

Step b2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carbonitrile

A drop of water and 2 ml (26 mmol) of trifluoroacetic acid were added to100 mg (0.26 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrile.After 16 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was distilled off under reduced pressure and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The residue wastriturated with 5 ml of chloroform, filtered off and then dried. Thisgave 30 mg (38% of theory) of2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carbonitrileas a yellow solid. m.p. 256-258° C. ¹H NMR (400 MHz, DMSO): δ[ppm]=3.79(8H), 7.36 (1H), 7.65-7.66 (1H), 7.68-7.69 (1H), 8.28 (1H), 8.49-8.51(1H), 13.42 (1H). LC-MS (method 1): m/z: [M+H]⁺=306.1, R_(t)=2.93 min.

Example 352-((R)-3-methylmorpholin-4-yl)-8-(-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrileStep a2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrile

Under argon, 4 mg (0.004 mmol) oftetrakis(triphenylphosphine)palladium(0) were added to a suspension of60 mg (0.114 mmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 14 mg (0.114 mmol) of zinc cyanide in 2ml of absolute dimethylformamide. The reaction mixture was stirred at100° C. for 15 min. For work-up, a mixture of 25 ml of water and 25 mlof 50 percent strength ammonia solution was added to the mixture. Theprecipitated solid was filtered off with suction and washed with 10 mlof water. The solid was then dried under reduced pressure. 35 mg (76% oftheory) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrilewere obtained as a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=405.3,R_(t)=3.53 min.

Step b2-((R)-3-methylmorpholin-4-yl)-8-(-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrile

1 ml (2 mmol) of 2N hydrochloric acid was added to a solution of 35 mg(0.087 mmol) of2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrilein 2 ml of methanol. The solution was stirred at 50° C. for 18 h. After18 h, LCMS showed complete removal of the protective group. Methanol wasdistilled off under reduced pressure and the residue that remained wasadjusted to pH 7 using sodium bicarbonate solution. A solid precipitatedout; this was separated off and washed with 10 ml of water. The solidwas then dried under reduced pressure. This gave 18 mg (58% of theory)of2-((R)-3-methylmorpholin-4-yl)-8-(-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrileas a yellow solid. LC-MS (method 1): m/z: [M+H]+=321.2, Rt=3.08 min.

Example 362-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carboxamideStep a2-morpholin-4-yl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxamide

47 mg (0.85 mmol) of potassium hydroxide in a drop of water were addedto a suspension of 300 mg (0.77 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carbonitrilein 15 ml of isopropanol, and the mixture was stirred at 70° C. for 6 h.The solvent was distilled off and the residue was used without furtherpurification for protective group removal. This gave2-morpholin-4-yl-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxamideas a yellow solid in a yield of 314 mg (100% of theory). LC-MS (method1): m/z: [M+H]⁺=409.3, R_(t)=2.62 min.

Step b2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carboxamide

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to95 mg (0.23 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxamide.After 2 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was distilled off under reduced pressure and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The precipitated solid was filtered off with suction anddried. The product was chromatographed [silica gel 60 (12 g, 30 μm);chloroform/methanol (1:1, 300 ml)]. This gave 20 mg (25% of theory) of2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine-4-carboxamideas a yellow solid. m.p. 282-285° C. ¹H NMR (400 MHz, DMSO, δ ppm): 3.79(8H), 7.36 (1H), 7.61 (2H), 7.83-7.84 (1H), 7.89 (1H), 8.23 (1H),8.37-8.39 (1H), 13.36 (1H).

Example 374-methanesulphonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineStep a potassium2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylate

3.3 g (8.45 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]-naphthyridine-4-carbonitrilewere suspended in 33 ml of 2-methoxyethanol, 1.4 g (25.4 mmol) ofpotassium hydroxide in 772 μl of water were added and the mixture wasstirred at 150° C. for 7 h. Since conversion was still incomplete, themixture was stirred at 130° C. for a further 14 h. For work-up, most ofthe solvent was removed. The residue was triturated with 10 ml ofisopropanol and 50 ml of diethyl ether. The resulting precipitatedyellow solid was filtered off and dried under reduced pressure. Thisgave 2.74 g (72% of theory) of potassium2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylateas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=410.3, R_(t)=3.03 min.

Step b methyl2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxylate

630 mg (1.41 mmol) of potassium2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-[1,7]naphthyridine-4-carboxylatewere suspended in 10 ml of tetrahydrofuran, 459 mg (1.41 mmol) ofcaesium carbonate and 102 μl (1.69 mmol) of methyl iodide were added andthe mixture was stirred at 80° C. for 32 h. For work-up, most of thesolvent was removed. 20 ml of water were added to the residue, and themixture was extracted three times with in each case 30 ml of chloroform.The combined organic phases were dried over sodium sulphate and thenconcentrated to dryness. This gave 405 mg (68% of theory) of methyl2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxylateas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=424.4, R_(t)=3.50 min.

Step c{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-yl}methanol

At 0° C. and under an atmosphere of argon, 178 mg (4.68 mmol) of lithiumaluminium hydride were added to a solution of 660 mg (1.56 mmol) ofmethyl2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxylatein 16 ml of absolute tetrahydrofuran, and the mixture was stirred at 0°C. for 30 min. With ice-cooling, 20 ml of saturated ammonium chloridesolution were added to the reaction mixture, and the mixture was thenextracted three times with in each case 30 ml of chloroform. Thecombined organic phases were dried over sodium sulphate and concentratedunder reduced pressure. This gave 570 mg (93% of theory) of{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-yl}methanolas a crude product. The latter consisted of two compounds. According to¹H NMR spectrum, this crude product contained 30% of{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-yl}methanoland 70% of a compound having 2 extra mass units. It was not possible toseparate the two products by chromatography, and therefore they wereused as crude product in the next step. LC-MS (method 1): m/z:[M+H]⁺=396.3, R_(t)=2.95 min.

Step d2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-ylmethylmethanesulphonate

Under argon and at 10° C., 56 μl (0.72 mmol) of methanesulphonylchloride were added dropwise to a solution of 260 mg (0.66 mmol) of{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-yl}methanoland 119 μl (0.86 mmol) of triethylamine in 10 ml of absolutetetrahydrofuran, and the mixture was stirred at 10° C. for 1 h. Theprecipitated solid was filtered off and the filtrate was concentratedunder reduced pressure. This gave 311 mg (100% of theory) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-ylmethylmethanesulphonate as a brown solid. This crude product was used withoutfurther purification for the next synthesis. LC-MS (method 1): m/z:[M+H]⁺=474.3, R_(t)=3.24 min.

Step e4-methanesulphonylmethyl-2-(morpholin-4-yl-)8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Sodium methylsulphinate was added a little at a time to a solution of311 mg (0.66 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-ylmethylmethanesulphonate in 10 ml of absolute dimethyl sulphoxide, and themixture was then stirred at 120° C. for 20 min. The mixture was dilutedwith 10 ml of water and then extracted three times with in each case 10ml of dichloromethane. The combined organic solutions were dried oversodium sulphate and then concentrated under reduced pressure. Theresidue was chromatographed [Puri-Flash, silica gel 60 (25 g, 30 μm);dichloromethane/methanol 95:5]. This gave 80 mg (27% of theory) of4-methanesulphonylmethyl-2-(morpholin-4-yl-)8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow solid. LC-MS (method 1): m/z: [M+H]⁺=458.3, R_(t)=2.89 min.

Step f4-methanesulphonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine

30 mg (0.07 mmol) of4-methanesulphonylmethyl-2-(morpholin-4-yl-)8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 1 ml of methanol, and 0.5 ml (1 mmol) of 2Nhydrochloric acid was added. After 1 h, LCMS showed complete removal ofthe protective group. Methanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The resulting precipitated solid was filtered offand dried under reduced pressure. This gave 24 mg (98% of theory) of4-methanesulphonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 272-274° C. ¹H NMR (400 MHz, DMSO): δ[ppm]=3.10(3H), 3.74-3.81 (8H), 5.00 (2H), 7.36 (1H), 7.64 (2H), 7.94 (1H), 8.40(3H), 13.31 (1H).

Example 38[2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine-4-yl]methanol

50 mg (0.126 mmol) of[2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-yl}methanolwere dissolved in 1 ml of methanol, and 0.5 ml (1 mmol) of 2Nhydrochloric acid was added. After 1 h, LCMS showed complete removal ofthe protective group. Methanol was distilled off under reduced pressureand the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 10 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and concentrated under reduced pressure. Theresidue was purified using a Flashmaster chromatography [silica gel 60(25 g, 30 μm); dichloromethane/methanol 95:5]. This gave 20 mg (51% oftheory) of[2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]-naphthyridine-4-yl]methanolas a yellow solid. ¹H NMR (400 MHz, DMSO): δ[ppm]=3.81 (8H), 4.95 (2H),7.47-7.48 (1H), 7.68 (1H), 7.89-7.92 (2H), 8.35-8.36 (1H), 13.31 (1H).LC-MS (method 1): m/z: [M+H]⁺=312.2, R_(t)=2.31 min.

Example 394-(1-methanesulphonycyclopropyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-(1-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-(2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl)-[1,7]naphthyridine

330 μl of 50 percent strength sodium hydroxide solution were added to asolution of 150 mg (0.328 mmol) of4-methanesulphonylmethyl-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine,28 μl (0.319 mmol) of 1,2-dibromoethane and 10 mg (0.032 mmol) oftetrabutylammonium bromide in 960 μl of absolute tetrahydrofuran, andthe mixture was then stirred at room temperature for 1 h. The colour ofthe suspension changed from dark-green to dark-brown. Another 28 μl(0.319 mmol) of 1,2-dibromoethane, 10 mg (0.032 mmol) oftetrabutylammonium bromide and 330 μl of 50 percent strength sodiumhydroxide solution were added, and the mixture was stirred at 60° C. for3 h. The mixture was diluted with 10 ml of water and then extractedthree times with in each case 10 ml of dichloromethane. The combinedorganic phases were dried over sodium sulphate and concentrated underreduced pressure. The residue was purified twice by columnchromatography on a Flashmaster [silica gel 60 (2×25 g, 30 μm),dichloromethane/methanol 95:5]. This gave 23 mg (15% of theory) of4-(1-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. The solid, which was impure, was used without furtherpurification for the next step. LC-MS (method 1): m/z: [M+H]⁺=484.2,R_(t)=2.75 min.

Step b4-(1-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]naphthyridine

0.5 ml of (1 mmol) of 2N hydrochloric acid was added to a solution of 23mg (0.048 mmol) of4-(1-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl)]-[1,7]naphthyridinein 1 ml of methanol. The solution was stirred at 50° C. for 18 h. After18 h, LCMS showed complete removal of the protective group. Methanol wasdistilled off under reduced pressure and the residue that remained wasadjusted to pH 7 using sodium bicarbonate solution. The aqueous phasewas extracted three times with in each case 10 ml of dichloromethane.The combined organic phases were dried over sodium sulphate andconcentrated under reduced pressure. This gave 18 mg (85% of theory) of4-(1-methanesulphonylcyclopropyl)-2-(morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]-naphthyridineas a yellow solid. m.p. 220-234° C. ¹H NMR (400 MHz, DMSO):δ[ppm]=1.39-2.09 (4H), 3.06 (3H), 3.79-3.80 (8H), 7.36 (1H), 7.61 (1H),7.82-7.88 (2H), 8.39-8.41 (1H), 13.36 (1H). LC-MS (method 1): m/z:[M+H]⁺=400.30, R_(t)=2.21 min.

Example 404-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-isopropoxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin

44 mg (0.31 mmol) of potassium carbonate were added to a solution of 100mg (0.26 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-oland 45 mg (0.26 mmol) of iodopropane in 6 ml of dry acetonitrile (MeCN).The suspension was stirred at 85° C. for 7 h. The course of the reactionwas monitored by LCMS. The solvent was removed and the residue thatremained was chromatographed [silica gel 60 (12 g, 30 μm); ethyl acetate(100 ml)]. This gave 90 mg (81% of theory) of4-isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=424.3, R_(t)=3.66 min.

Step b4-Isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to80 mg (0.19 mmol) of4-isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine.After 10 min, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed under reduced pressure and the residuethat remained was adjusted to pH 7 using sodium bicarbonate solution.The aqueous phase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (12 g, 30 μm); ethyl acetate (100 ml)].This gave 40 mg (59% of theory) of4-isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow foam. m.p. 73-74° C. ¹H NMR (400 MHz, CDCl₃, δ ppm): 1.48(6H), 3.64-3.67 (4H), 3.89-3.92 (4H), 4.75-4.78 (1H), 6.37 (1H), 7.23(1H), 7.67 (1H), 7.71 (1H), 8.38 (1H). LC-MS (method 1): m/z:[M+H]⁺=340.3, R_(t)=2.95 min.

Example 412-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(1H-pyrrol-2-yl)-1,7-naphthyridineStep a tert-butyl2-[2-(morpholin-4-yl)-4-(propan-2-yloxy)-1,7-naphthyridin-8-yl]-1H-pyrrole-1-carboxylate

Under argon, 20 mg (0.024 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 75 mg (0.24 mmol)8-chloro-2-(morpholin-4-yl)-4-(propan-2-yloxy)-1,7-naphthyridine and 57mg (0.27 mmol) [1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]boronic acid in 2ml acetonitrile and 2 ml 2M aqueous solution of potassium carbonate. Themixture was stirred in a microwave oven at 130° C. for 10 minutes. Aftercooling, DCM was added and the mixture was filtered using a Whatmanfilter. The organic phase was concentrated and the residue was purifiedby HPLC separation (Autopurifier: basic conditions) to give 35 mg (0.08mmol) of the desired product. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=0.92(9H), 1.37 (6H), 3.52 (4H), 3.63 (4H), 5.05 (1H), 6.29 (1H), 6.39 (1H),6.76 (1H), 7.37 (1H), 7.63 (1H), 8.20 (1H).

Step b2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(1H-pyrrol-2-yl)-1,7-naphthyridine

7 μl (0.096 mmol) TFA were added to a solution of 9 mg (0.020 mmol)tert-butyl2-[2-(morpholin-4-yl)-4-(propan-2-yloxy)-1,7-naphthyridin-8-yl]-1H-pyrrole-1-carboxylatein 2 ml DCM and the reaction mixture was stirred at room temperature for150 minutes. Additional 7 μl (0.096 mmol) TFA was added and the reactionmixture was stirred overnight. Additional 23 μl (0.32 mmol) TFA wasadded and the reaction mixture was stirred for 8 hours. The mixture wasbasified by addition of aqueous sodium bicarbonate solution andextracted with DCM (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to give 9 mg (0.027 mmol) of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ[ppm]=1.50 (6H), 3.70 (4H),3.96 (4H), 4.80 (1H), 6.41 (2H), 7.03 (1H), 7.48 (1H), 7.61 (1H), 8.31(1H), 11.53 (1H).

Example 424-(3-(S-methylsulfonimidoyl)propoxy)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2,2,2-trifluoro-N-[(3-hydroxypropyl)(methyl)oxido-λ⁶-sulfanylidene]acetamide

A mixture of 1.00 g (2.83mmol)N-[{3-[(benzyloxy)methoxy]propyl}(methyl)oxido-λ⁶-sulfanylidene]-2,2,2-trifluoroacetamideand 0.75 g palladium on charcoal (10%) in 100 ml ethanol was stirredunder a hydrogen atmosphere for 90 minutes at 80° C. 0.50 g palladium oncharcoal (10%) are added and the mixture is stirred for additional 3hours under a hydrogen atmosphere at 80° C. After cooling, the reactionmixture was filtered and the filtrate was concentrated to give 0.61 g ofthe desired product that was used without further purification. ¹H-NMR(400 MHz, CDCl₃): δ [ppm]=2.18 (2H), 3.41 (3H), 3.61 (1H), 3.72 (1H),3.86 (2H).

Step b2,2,2-trifluoro-N-{methyl[3-({2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propyl]oxido-λ⁶-sulfanylidene}acetamide

A solution of 26 μl (0.13 mmol) diisopropyl azodicarboxylate in 0.1 mlTHF was added dropwise to a mixture of 50 mg (0.13 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol,28 mg crude2,2,2-trifluoro-N-[(3-hydroxypropyl)(methyl)oxido-λ⁶-sulfanylidene]acetamideand 34 mg (0.13 mmol) triphenylphosphine in 0.5 ml THF and the batch wasstirred at room temperature for 6 hours. 94 mg (0.36 mmol)triphenylphosphine and 71 μl (0.36 mmol) diisopropyl azodicarboxylatewere added and the mixture was stirred at room temperature overnight.Finally, 34 mg (0.13 mmol) triphenylphosphine and 26 μl (0.13 mmol)diisopropyl azodicarboxylate were added and the mixture was stirred for6 hours before it was concentrated. The residue was purified by columnchromatography on silica gel (DCM to DCM/ethanol 15%) to give 34 mg ofthe product with approximately 70% purity.

Step c4-[3-(S-methylsulfonimidoyl)propoxy]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

39 mg (0.29 mmol) potassium carbonate was added to a solution of 34 mg2,2,2-trifluoro-N-{methyl[3-({2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propyl]oxido-λ⁶-sulfanylidene}acetamide(purity approximately 70%) in 1.2 ml methanol and the reaction mixturewas stirred at room temperature for 90 minutes. Aqueous sodium chloridesolution was added and the mixture was extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated to give 27 mg of the desired product with a purity ofapproximately 66%.

Step d4-(3-(S-methylsulfonimidoyl)propoxy)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.06 ml (0.12 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 27 mg4-[3-(S-methylsulfonimidoyl)propoxy]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine (purityapproximately 66%) in 0.25 ml methanol and the reaction mixture wasstirred at room temperature for 1 hour. The mixture was basified byaddition of an aqueous sodium bicarbonate solution and extracted withethyl acetate (2×). The combined organic phases were filtered using aWhatman filter and concentrated. The residue was purified by preperativeHPLC (Autopurifier: acidic conditions) to give 3 mg (0.007 mmol) of thedesired product. ¹H-NMR (400 MHz, DMSO-d6): δ[ppm]=2.32 (2H), 2.99 (3H),3.31 (2H), 3.75 (4H), 3.80 (4H), 4.41 (2H), 6.90 (1H), 7.38 (1H), 7.62(1H), 7.81 (1H), 8.35 (1H), 13.37 (1H).

Example 434-ethoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine Stepa4-ethoxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

44 mg (0.31 mmol) of potassium carbonate were added to a solution of 100mg (0.26 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-oland 21 μl (0.26 mmol) of iodoethane in 6 ml of dry acetonitrile (MeCN).The suspension was stirred at 85° C. for 2 h. The course of the reactionwas monitored by LCMS. The solvent was removed and the residue thatremained was reacted further without purification. LC-MS (method 1):m/z: [M+H]⁺=410.3, R_(t)=3.53 min.

Step b4-ethoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

One drop of water and 1 ml (13 mmol) of trifluoroacetic acid were addedto 107 mg (0.26 mmol) of4-ethoxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 1 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed under reduced pressure and the residuethat remained was adjusted to pH 7 using sodium bicarbonate solution.The aqueous phase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. 5 ml of methanol were addedto the residue. The resulting precipitated solid was filtered off andthen dried. This gave 25 mg (29% of theory) of4-ethoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine as ayellow solid. m.p. 173-175° C. ¹H NMR (400 MHz, CDCl₃, δ ppm): 1.57-1.61(3H), 3.70-3.72 (4H), 3.92-3.95 (4H), 4.22-4.27 (2H), 6.41 (1H), 7.25(2H), 7.70 (1H), 7.75 (1H), 8.42 (1H). LC-MS (method 1): m/z:[M+H]⁺=326.3, R_(t)=2.81 min.

Example 444-methoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine Stepa4-methoxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

44 mg (0.31 mmol) of potassium carbonate were added to a solution of 100mg (0.26 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-oland 32 μl (0.26 mmol) of methyl iodide in 6 ml of dry acetonitrile. Thesuspension was stirred at 85° C. for 2 h. The course of the reaction wasmonitored by LCMS. The solvent was removed and the residue that remainedwas reacted further without purification. LC-MS (method 1): m/z:[M+H]*=396.3, R_(t)=3.33 min.

Step b4-methoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to103 mg (0.26 mmol) of4-methoxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 10 min, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed under reduced pressure and the residuethat remained was adjusted to pH 7 using sodium bicarbonate solution.The aqueous phase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. The residue was trituratedwith 5 ml of methanol. The resulting precipitated solid was filtered offand then dried. This gave 30 mg (35% of theory) of4-methoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine as ayellow solid. m.p. 234-235° C. ¹H NMR (400 MHz, CDCl₃, δ ppm): 3.67-3.69(4H), 3.91-3.93 (4H), 4.01 (3H), 6.36 (1H), 7.25 (1H), 7.68 (2H), 8.40(1H). LC-MS (method 1): m/z: [M+H]⁺=312.3, R_(t)=2.60 min.

Example 452-methyl-1-([2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]oxy)propan-2-olStep a2-methyl-1-({2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propan-2-ol

87 mg (0.63 mmol) potassium carbonate was added to a mixture of 60 mg(0.16 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-oland 102 mg (0.94 mmol) 1-chloro-2-methylpropan-2-ol in 5.0 ml ethanoland 0.5 ml water and the mixture was stirred at 70° C. for 20 hours. 51mg (0.47 mmol) 1-chloro-2-methylpropan-2-ol and 44 mg (0.32 mmol)potassium carbonate were added and the mixture was stirred foradditional 24 hours at 70° C. After cooling, the reaction mixture wasdiluted with water and extracted with DCM (2×). The combined organicphases were dried (MgSO₄), filtered and concentrated. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 17mg (0.04 mmol) of the desired product.

Step b2-methyl-1-([2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]oxy)propan-2-ol

0.04 ml (0.08 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 16 mg2-methyl-1-({2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propan-2-olin 0.2 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated to give 5 mg (0.01 mmol) of the desired product. ¹H-NMR(400 MHz, CDCl₃): δ[ppm]=1.50 (6H), 3.72 (4H), 3.95 (4H), 4.02 (2H),6.45 (1H), 7.28 (1H), 7.72 (1H), 7.73 (1H), 8.44 (1H),

Example 462-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(tetrahydrofuran-2-ylmethoxy)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(259 mg, 0.43 mmol), 2-(bromomethyl)tetrahydrofuran (126 mg, 0.68 mmol)and Caesiumcarbonate (181 mg, 0.56 mmol) in DMF (1.63 ml) was heated ina sealed tube in the microwave at 100° C. for one hour. The reactionmixture was allowed to cool to ambient temperature, a solution ofconcentrated aqueous HCl (0.49 ml) was added and the reaction wasstirred at this temperature for two hours. The solvent was evaporatedunder reduced pressure, the residue was taken up in dichloromethane (10ml) and water (10 ml). The layers were separated and the aqueous layerwas extracted with dichloromethane (2×10 ml). The combined organiclayers were dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 4% yield (7 mg). ¹H-NMR(400 MHz, DMSO): δ[ppm]=1.75-2.15 (4H), 3.73-3.88 (10H), 4.25-4.36 (3H),6.94 (1H), 7.39 (1H), 7.70 (1H), 7.75 (1H), 8.36 (1H), 13.52 (1H).

Example 473-([2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]oxy)dihydrofuran-2(3H)-one

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(242 mg, 0.40 mmol), 3-bromodihydrofuran-2(3H)-one (99 mg, 0.60 mmol)and Caesiumcarbonate (169 mg, 0.52 mmol) in DMF (2 ml) was heated in asealed tube in the microwave at 100° C. for one hour. The reactionmixture was allowed to cool to ambient temperature, a solution ofconcentrated aqueous HCl (0.49 ml) was added and the reaction wasstirred at this temperature for two hours. The solvent was evaporatedunder reduced pressure, the residue was taken up in dichloromethane (10ml) and water (10 ml). The layers were separated and the aqueous layerwas extracted with dichloromethane (2×10 ml). The combined organiclayers were dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 4% yield (7 mg). ¹H-NMR(400 MHz, DMSO): δ[ppm]=2.91-2.95 (1H), 3.67-3.80 (9H), 4.36 (1H), 4.55(1H), 5.80 (1H), 7.08 (1H), 7.36 (1H), 7.61 (1H), 7.70 (1H), 8.34 (1H),13.33 (1H).

Example 484-[(3-methyl-1,2-oxazol-5-yl)methoxy]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(283 mg, 0.47 mmol), 5-(bromomethyl)-3-methyl-1,2-oxazole (123 mg, 0.70mmol) and Caesiumcarbonate (197 mg, 0.61 mmol) in DMF (1.78 ml) washeated in a sealed tube in the microwave at 100° C. for one hour. Thereaction mixture was allowed to cool to ambient temperature, a solutionof concentrated aqueous HCl (0.7 ml) was added and the reaction wasstirred at this temperature for two hours. The solvent was evaporatedunder reduced pressure, the residue was taken up in dichloromethane (10ml) and water (10 ml). The layers were separated and the aqueous layerwas extracted with dichloromethane (2×10 ml). The combined organiclayers were dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 3% yield (6 mg). ¹H-NMR(400 MHz, DMSO): δ[ppm]=2.27 (3H), 3.76 (8H), 5.57 (2H), 6.65 (1H), 7.06(1H), 7.36 (1H), 7.61 (1H), 7.69 (1H), 8.32 (1H), 13.35 (1H).

Example 494-[(5-methyl-1,2-oxazol-3-yl)methoxy]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(264 mg, 0.35 mmol), 3-(bromomethyl)-5-methyl-1,2-oxazole (91 mg, 0.51mmol) and Caesiumcarbonate (147 mg, 0.45 mmol) in DMF (1.32 ml) washeated in a sealed tube in the microwave at 100° C. for one hour. Thereaction mixture was allowed to cool to ambient temperature, a solutionof concentrated aqueous HCl (0.51 ml) was added and the reaction wasstirred at this temperature for two hours. The solvent was evaporatedunder reduced pressure, the residue was taken up in dichloromethane (10ml) and water (10 ml). The layers were separated and the aqueous layerwas extracted with dichloromethane (2×10 ml). The combined organiclayers were dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude product was purified by HPLC chromatography (acidicconditions). The title compound was obtained in 10 mg yield. ¹H-NMR (400MHz, DMSO): δ[ppm]=2.46 (3H), 3.77 (8H), 5.49 (2H), 6.52 (1H), 7.09(1H), 7.39 (1H), 7.62 (1H), 7.72 (1H), 8.34 (1H), 13.38 (1H).

Example 504-benzyloxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-benzyloxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

44 mg (0.31 mmol) of potassium carbonate were added to a solution of 100mg (0.26 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-ol,31 μl (0.26 mmol) of benzyl bromide and 4 mg (0.024 mmol) of potassiumiodide in 6 ml of dry acetonitrile (MeCN). The suspension was stirred at85° C. for 2 h. The course of the reaction was monitored by LCMS. Thesolvent was removed and the residue that remained was chromatographed[silica gel 60 (12 g, 30 μm); ethyl acetate (100 ml)]. This gave 90 mg(73% of theory) of4-benzyloxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LC-MS (method 1): m/z: [M+H]⁺=472.3, R_(t)=3.86 min.

Step b4-benzyloxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 1 ml (13 mmol) of trifluoroacetic acid were added to90 mg (0.19 mmol) of4-benzyloxy-2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 10 min, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was removed under reduced pressure and the residuethat remained was adjusted to pH 7 using sodium bicarbonate solution.The aqueous phase was extracted three times with in each case 20 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then concentrated to dryness. 5 ml of methanol were addedto the residue. The resulting precipitated solid was filtered off andthen dried. This gave 40 mg (54% of theory) of4-benzyloxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine asa yellow solid. m.p. 217-219° C. ¹H NMR (400 MHz, CDCl₃, δ ppm):3.69-3.71 (t, 4H), 3.92-3.94 (t, 4H), 5.29 (s, 2H), 6.52 (s, 1H),7.41-7.51 (m, 6H), 7.70 (d, 1H), 7.79 (d, 1H), 8.42 (d, 1H). LC-MS(method 1): m/z: [M+H]⁺=388.3, R_(t)=3.23 min.

Example 514-Isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-Isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

84 mg (0.61 mmol) of potassium carbonate were added to a solution of 200mg (0.51 mmol) of2-[(R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-oland 101 μl (1.01 mmol) of iodopropane in 4 ml of dry acetonitrile. Thesuspension was stirred at 85° C. for 3 h. The course of the reaction wasmonitored by LCMS. The solvent was removed and the residue that remainedwas chromatographed [silica gel 60 (25 g 30 μm); ethyl acetate (100ml)]. This gave 60 mg (27% of theory) of4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a yellow oil. LCMS (method 1): m/z: [M+H]⁺=438.4, R_(t)=3.73 min.

Step b4-Isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

80 mg (0.18 mmol) of4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 2 ml of methanol, and 2 ml (4 mmol) of 2N hydrochloricacid were added. After 1 h, LCMS showed complete removal of theprotective group. Ethanol was distilled off under reduced pressure andthe residue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (25 g, 30 μm); ethyl acetate (100 ml)].This gave 45 mg (70% of theory) of4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. m.p. 75-77° C. ¹H NMR (400 MHz, CDCl₃):δ[ppm]=1.38-1.41 (3H), 1.47-1.49 (6H), 3.44-3.51 (1H), 3.65-3.72 (1H),3.81-3.91 (3H), 4.01-4.15 (1H), 4.30-4.33 (1H), 4.74-4.79 (1H), 6.37(1H), 7.22 (1H), 7.67-7.68 (1H), 7.70-7.72 (1H), 8.36-8.37 (1H). LC-MS(method 1): m/z: [M+H]⁺=354.4, R_(t)=2.92 min.

Example 52 tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butyl]carbamateStep a tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-[(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)butyl]carbamate

2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol (0.41, 1.0mmol, 1 eq.) was solubilized in DMF (12 mL). 4-(Boc-amino)butyl bromide(0.53 g, 2.1 mmol, 2 eq.) and K₂CO₃ (0.72 g 5.2 mmol, 5 eq.) were addedto the mixture. The reaction was stirred at rt for 16 hours. Thesuspension was diluted with EtOAc and filtered. The organic phase wasconcentrated under reduced pressure and the crude material purified byflash chromatography (gradient Hex/EtOAc 9/1 to 100% EtOAc). The desiredproduct was obtained in 87% yield (0.52 g). ¹H-NMR (400 MHz, DMSO-d₆):δ[ppm]: 1.14-1.24 (3H), 1.38 (9H), 1.41-1.69 (5H), 1.80-1.90 (2H), 1.99(2H), 2.30-2.42 (1H), 3.03 (2H), 3.10-3.29 (2H), 3.40-3.52 (1H), 3.73(3H), 3.91-3.99 (1H), 4.12 (1H), 4.27 (2H), 4.45-4.58 (1H), 6.01-6.13(1H), 6.75 (1H), 6.84-6.95 (2H), 7.60 (1H), 7.75 (1H), 8.35 (1H). LC-MS(Method 3): m/z: [M+H]⁺=567, R_(t)=1.31 min.

Step b tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butyl]carbamate

Tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)butyl]carbamate(20 mg, 0.035 mmol, 1 eq.) was solubilized in CH₂Cl₂ (0.5 mL) and water(0.5 mL). Acetic acid (0.12 mL, 1.8 mmol, 50 eq.) was added. After 2hours, formic acid (0.10 mL, 2.6 mmol, 75 eq.) was added and thereaction was stirred at rt for 1 hour. The reaction mixture wasneutralised by addition of sat. NaHCO₃ and the aqueous phase wasextracted 3 times with CH₂Cl₂. The organic phase was dried (siliconfilter) and concentrated under reduced pressure. The crude mixture waspurified by flash column chromatography (gradient 1/1Hex/EtOAc to 100%EtOAc to 9/1 EtOAc/MeOH). The desired product was obtained in 68% yield(12 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.20-1.30 (4H), 1.37 (9H),1.57-1.67 (2H), 1.80-1.89 (2H), 3.03 (2H), 3.56 (1H), 3.71 (1H), 3.83(1H), 4.05 (1H), 4.15 (1H), 4.27 (2H), 4.56-4.65 (1H), 6.81 (1H), 6.89(1H), 7.37 (1H), 7.60 (1H), 7.71 (1H), 8.32 (1H), 13.37 (1H). LC-MS(Method 3): m/z: [M+H]⁺=483, R_(t)=0.98 min.

Example 534-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a8-chloro-4-methoxy-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridine

320 mg (2.32 mmol) of potassium carbonate were added to a solution of540 mg (1.93 mmol) of8-chloro-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridin-4-ol and 144μl (2.32 mmol) of iodomethane in 10 ml of acetonitrile. The suspensionwas stirred at 80° C. for 5 h. For work-up, 20 ml of water were added tothe mixture. The aqueous phase was extracted three times with in eachcase 30 ml of dichloromethane. The combined organic phases were driedover sodium sulphate and then concentrated to dryness. The crude productwas separated by column chromatography [Puri-Flash, silica gel 60 (25 g,30 μm); ethyl acetate (200 ml)]. This gave 270 mg (48%) of8-chloro-4-methoxy-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridine asa yellow oil. LCMS (method 1): m/z: [M+H]⁺=294.3, R_(t)=3.43 min.

Step b4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 145 mg (0.18 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) and 1.15 g (3.54 mmol) of caesium carbonate wereadded to a suspension of 260 mg (0.89 mmol) of8-chloro-4-methoxy-2-((R)-3-methylmorpholin-4-yl)-[1,7]naphthyridine and369 mg (1.33 mmol) of1-(tetrahydropyran-2-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-pyrazolein 12 ml of absolute 1,4-dioxane. The reaction mixture was stirred at95° C. for 6 h. The brown reaction solution was purified via columnchromatography [silica gel 60 (30 g); ethyl acetate (200 ml)]. In thismanner, 360 mg (99% of theory) of4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere isolated as a yellow solid. LCMS (method 1): m/z: [M+H]⁺=410.3,R_(t)=3.46 min.

Step c4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

360 mg (0.88 mmol) of4-isopropoxy-2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere dissolved in 10 ml of methanol, and 2 ml (4 mmol) of 2Nhydrochloric acid were added. After 1 h, LCMS showed complete removal ofthe protective group. The methanol was distilled off under reducedpressure and the residue that remained was adjusted to pH 7 using sodiumbicarbonate solution. The aqueous phase was extracted three times within each case 20 ml of dichloromethane. The combined organic phases weredried over sodium sulphate and then concentrated to dryness. 5 ml ofethyl acetate were added to the residue. The resulting precipitatedsolid was filtered off and dried. This gave 120 mg (42% of theory) of4-methoxy-2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineand 100 mg (35% of theory) of slightly contaminated product as a beigesolid. m.p. 193-195° C. ¹H NMR (400 MHz, DMSO): δ[ppm]=1.27-1.29 (3H),3.31-3.32 (1H), 3.56-3.57 (1H), 3.70-3.73 (1H), 3.82-3.85 (1H),3.85-4.06 (1H), 4.04 (3H), 4.15-4.17 (1H), 4.61-4.63 (1H), 6.82 (1H),7.37 (1H), 7.61 (1H), 7.70-7.71 (1H), 8.32-8.33 (1H), 13.36 (1H).

Example 54 tert-butyl[3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)propyl]carbamateStep a tert-butyl[3-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propyl]carbamate

2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(0.37 g, 0.93 mmol, 1 eq.) was solubilized in DMF (6 mL).N-Boc-3-chloropropylamine (0.36 g,& 1.9 mmol, 2 eq.) and K₂CO₃ (0.64 g4.7 mmol, 5 eq.) were added to the mixture. The reaction was stirred at120° C. for 16 hours. After cooling to rt, the mixture was filtered, thesolid was washed with CH₂Cl₂ and the filtrate was concentrated underreduced pressure. The crude material was purified by flashchromatography (gradient 100% Hexane to 100% EtOAc). The desired productwas obtained in 70% yield (0.36 g). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]:1.13-1.23 (3H), 1.36 (9H), 1.40-1.64 (3H), 1.89-2.04 (4H), 2.30-2.41(1H), 3.10-3.29 (4H), 3.40-3.51 (1H), 3.57-3.79 (3H), 3.92-3.99 (1H),4.07-4.17 (1H), 4.27 (2H), 4.45-4.58 (1H), 6.01-6.13 (1H), 6.71-6.77(1H), 6.88-6.98 (2H), 7.60 (1H), 7.77 (1H), 8.36 (1H). LC-MS (Method 3):m/z: [M+H]⁺=553 R_(t)=1.23 min.

Step b tert-butyl[3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)propyl]carbamate

Tert-butyl[3-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propyl]carbamate(20 mg, 0.036 mmol, 1 eq.) was solubilized in CH₂Cl₂ (0.5 mL) and water(0.5 mL). Formic acid (0.10 mL, 2.7 mmol, 75 eq.) was added and thereaction was stirred at rt for 1 hour. The reaction mixture wasneutralised by addition of sat. NaHCO₃ and the aqueous phase wasextracted 3 times with CH₂Cl₂. The organic phase was dried (siliconfilter) and concentrated under reduced pressure. The desired product wasobtained without further purification in 86% yield (15 mg). ¹H-NMR (400MHz, DMSO-d₆): δ[ppm]: 1.26 (3H), 1.36 (9H), 1.93-2.02 (2H), 3.18 (2H),3.25-3.30 (1H), 3.55 (1H), 3.70 (1H), 3.82 (1H), 4.05 (1H), 4.15 (1H),4.27 (2H), 4.55-4.63 (1H), 6.80 (1H), 6.95 (1H), 7.37 (1H), 7.61 (1H),7.73 (1H), 8.33 (1H), 13.37 (1H). LC-MS (Method 3): m/z: [M+H]⁺=469,R_(t)=0.96 min.

Example 552-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)ethanamine

Tert-butyl[2-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)ethyl]carbamate(0.36 g, 0.67 mmol, 1 eq.) was solubilised in CH₂Cl₂ (4.3 mL) andtrifluoroacetic acid (2.6 mL, 33 mmol, 50 eq.) was added. The reactionwas stirred for 16 h at rt and quenched with sat NaHCO₃. The aqueousphase was extracted 3 times with EtOAc and the organic phase was washedwith H₂O and sat. NaCl. The organic phase was dried (silicon filter) andconcentrated under reduced pressure. The crude material was purified byflash column chromatography (gradient hex/EtOAc:7/3 to 100% EtOAc toEtOAc/EtOH:9/1). The combined fractions were concentrated and EtOH wasadded. The suspension was filtered and the solid was dried under reducedpressure. The desired product was obtained in 11% yield (26 mg). ¹H-NMR(400 MHz, DMSO-d₆): δ[ppm]: 1.26 (3H), 3.24-3.31 (1H), 3.55 (1H),3.67-3.78 (3H), 3.83 (1H), 4.05 (1H), 4.17 (1H), 4.32-4.41 (3H),4.57-4.67 (1H), 6.85 (1H), 7.37 (1H), 7.60 (1H), 7.75 (1H), 8.33 (1H),9.77 (1H), 13.37 (1H).

Example 56 tert-butyl[2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)ethyl]carbamateStep a tert-butyl[2-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)ethyl]carbamate

2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(0.40 g, 1.0 mmol, 1 eq.) was solubilised in DMF (10 mL). K₂CO₃ (0.70 g,5.0 mmol, 2 eq.) and tert-butyl (2-bromoethyl)carbamate (0.45 g, 2.0mmol, 2 eq.) were sequentially added. The reaction was stirred for 16hours at rt. The reaction was then diluted with EtOAc and the suspensionwas filtered. The filtrate was concentrated under reduced pressure andpurified ny flash column chromatography (gradient Hex/EtOAc: 8/2 tohex/EtOAc 1/9). The desired product was obtained in 84% yield (0.46 g).¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.19 (3H), 1.32-1.49 (11H), 1.49-1.64(1H), 1.89-2.04 (2H), 2.30-2.40 (1H), 3.10-3.30 (2H), 3.40-3.51 (3H),3.73 (3H), 3.90-3.99 (1H), 4.09-4.18 (1H), 4.19-4.23 (2H), 4.47-4.59(1H), 6.01-6.13 (1H), 6.78 (1H), 6.92 (1H), 7.21 (1H), 7.60 (1H), 7.88(1H), 8.34 (1H). LC-MS (Method 3): m/z: [M+H]⁺=539, R_(t)=1.23 min.

Step b tert-butyl[2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)ethyl]carbamate

Tert-butyl[2-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)ethyl]carbamate(0.10 g, 0.19 mmol, 1 eq.) was solubilised in CH₂Cl₂ (1.2 mL) andtrifluoroacetic acid (0.29 mL, 3.7 mmol, 20 eq.) was added. The reactionwas stirred for 1 h at rt and quenched with sat NaHCO₃. The suspensionwas filtered and the solid was purified by flash column chromatography(gradient from hex/EtOAc: 1/1 to 100% EtOAc to 100% EtOH). The desiredproduct was obtained in 28% yield (24 mg). ¹H-NMR (400 MHz, DMSO-d₆):δ[ppm]: 1.26 (3H), 1.39 (9H), 3.24-3.30 (1H), 3.46 (2H), 3.52-3.62 (1H),3.70 (1H), 3.82 (1H), 3.99-4.09 (1H), 4.17 (1H), 4.22 (2H), 4.61 (1H),6.84 (1H), 7.21 (1H), 7.37 (1H), 7.60 (1H), 7.83 (1H), 8.31 (1H), 13.36(1H).

Example 574-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butan-1-amine

Tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)butyl]carbamate(0.10 g, 0.18 mmol, 1 eq.) was solubilised in CH₂Cl₂ (1.1 mL) and TFA(0.27 mL, 3.5 mmol, 20 eq.) was added. The reaction was stirred at rtfor 30 min and quenched with sat. NaHCO₃. The suspension was filteredand the solid was dried under reduced pressure. The desired product wasobtained without further purification in quantitative yield. ¹H-NMR (400MHz, DMSO-d₆): δ[ppm]: ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.27 (3H),1.73-1.84 (2H), 1.88-1.98 (2H), 2.86-2.95 (2H), 3.56 (1H), 3.71 (1H),3.84 (1H), 4.02-4.10 (1H), 4.15 (1H), 4.30 (2H), 4.61 (1H), 6.82 (1H),7.37 (1H), 7.57 (1H), 7.61 (2H), 7.71 (1H), 8.33 (1H), 13.36 (1H).

Example 582-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-Isopropoxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

8-Chloro-2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-naphthyridine(0.10 g, 0.28 mmol, 1 eq.) was solubilised in DME (3 mL).1-(2-Tetrahydropyranyl)-1H-pyrazole-5-boronic acid pinacol ester (0.24g, 0.84 mmol, 3 eq.), K₂CO₃ (0.11 & 0.84 mmol, 3 eq.),bis(triphenylphosphin)palladium(II)chloride (20 mg, 0.030 mmol, 0.1 eq.)and H₂O (1.5 mL) were added sequentially. The reaction was heated undermicrowave irradiation at 130° C. for 10 min. The crude reaction mixturewas filtered through a silicon filter and concentrated under reducedpressure. The crude mixture was purified by preparative HPLC(H₂O(HCOOH)/CH₃CN: 50:50 to 30:70). The purified product wasconcentrated under reduced pressure, solubilised in CH₂Cl₂ and washedtwo times with sat. NaHCO₃. The organic phase was dried (MgSO₄) andconcentrated under reduced pressure. The desired product was obtained asa solid in 54% yield (56 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.37(6H), 1.41 (6H), 3.69 (2H), 3.88 (2H), 4.50 (2H), 5.07 (1H), 6.70 (1H),7.36 (1H), 7.60 (1H), 7.69 (1H), 8.29 (1H), 13.38 (1H).

Example 592-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-Isopropoxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

8-Chloro-2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-1,7-naphthyridine(40 mg, 0.12 mmol, 1 eq.), 1-(2-tetrahydropyranyl)-1H-pyrazole-5-boronicacid pinacol ester (50 mg, 0.18 mmol, 1.5 eq.), K₂CO₃ (2 M in H₂O, 0.18mL, 0.36 mmol, 3 eq.) and bis(triphenylphosphin)palladium(II)chloride(8.5 mg, 0.011 mmol, 0.1 eq.) were added sequentially to DME (1.1 mL).The reaction was heated under microwave irradiation at 130° C. for 10min. The reaction mixture was filtered through a silicon filter andconcentrated under reduced pressure. The crude mixture was purified bypreparative HPLC (H₂O(HCOOH)/CH₃CN:48:52 to 68:32). The desired productwas obtained in 20% yield (9.8 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]:1.26 (6H), 1.41 (6H), 3.67 (2H), 4.11 (2H), 4.22-4.31 (2H), 4.99-5.09(1H), 6.83 (1H), 7.44 (1H), 7.61 (1H), 7.73 (1H), 8.36 (1H), 13.28-13.56(1H).

Example 602-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-1,7-naphthyridine

75 mg (0.20 mmol) of4-(3,6-dihydro-2H-pyran-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridinewere dissolved in 50 ml of methanol, 50 mg of palladium/carbon (10percent) were added and the mixture was hydrogenated at 2 bar at roomtemperature for 3 h. The reaction solution was then filtered throughcelite and concentrated under reduced pressure. The residue wastriturated with methanol, the solid was filtered off and dried underreduced pressure. This gave2-(morpholin-4H-pyrazo-4-)-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-1,7-naphthyridinein a yield of 30 mg (40% of theory). m.p. 303-304° C. ¹H NMR (400 MHz,DMSO-d₆): δ[ppm]=1.76 (2H), 1.89 (2H), 3.53 (1H), 3.63 (2H), 3.77 (8H),4.01 (2H), 7.36 (2H), 7.61 (1H), 7.88 (1H), 8.38 (1H), 13.33 (1H).

Example 61 2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride Step a2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

Under argon, 40 mg (0.05 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 635 mg (1.95 mmol) of caesiumcarbonate were added to a suspension of 250 mg (0.49 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yltrifluoromethanesulphonate and 205 mg (0.97 mmol)3,6-dihydro-2H-pyran-4-boronic acid pinacol ester in 5.0 ml of absolutedioxane. The reaction mixture was stirred at 110° C. for 4 h. Themixture was chromatographed directly without work-up [silica gel 60 (25g, 30 μm); ethyl acetate (100 ml)]. This gave 30 mg (17% of theory) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridineas a colourless oil. LC-MS (method 1): m/z: [M+H]⁺=366.3, R_(t)=3.09min.

Step b 2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

A drop of water and 0.5 ml (6.5 mmol) of trifluoroacetic acid were addedto 30 mg (0.08 mmol) of2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine.After 1 h, LCMS showed complete removal of the protective group. Thetrifluoroacetic acid was distilled off under reduced pressure and theresidue that remained was adjusted to pH 7 using sodium bicarbonatesolution. The aqueous phase was extracted three times with in each case20 ml of dichloromethane. The combined organic phases were dried oversodium sulphate and then concentrated to dryness. The residue waschromatographed [silica gel 60 (12 g, 30 μm); chloroform (100 ml)]. Thisgave 20 mg (87% of theory) of2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine as a yellowsolid. Since the latter was still impure, the correspondinghydrochloride was prepared. LC-MS (method 1): m/z: [M+H]⁺=282.3,R_(t)=2.42 min.

Step c 2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridinehydrochloride

20 mg (0.07 mmol) of2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine were dissolvedin 3.0 ml of 2-butanol and 28 μl (0.21 mmol) of trimethylchlorosilanewere added. The reaction solution was stirred at room temperature for 1h. The precipitated solid was filtered off and then dried. This gave 17mg (75% of theory) of2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine hydrochlorideas a yellow solid. m.p. 151-153° C. ¹H NMR (400 MHz, DMSO):δ[ppm]=3.80-3.85 (8H), 7.61-7.62 (1H), 7.89-7.91 (1H), 8.11-8.13 (2H),8.33-8.34 (1H), 8.41-8.43 (1H).

Example 624-chloro-2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine Step amethyl 3-tert-butoxycarbonylamino-2-chloroisonicotinate

Under argon and at room temperature, 1.92 g (8.7 mmol) of di-tert-butyldicarbonate and 244 mg (2 mmol) of 4-dimethylaminopyridine were added toa solution of 1.49 g (8 mmol) of methyl 3-amino-2-chloroisonicotinate in20 ml of dry tetrahydrofuran. The mixture was stirred at roomtemperature for 16 h. For work-up, the reaction mixture was adjusted topH 7 using 2N hydrochloric acid. The resulting precipitated solid wasfiltered off with suction and washed with 10 ml of water. In thismanner, methyl 3-tert-butoxycarbonylamino-2-chloroisonicotinate wasobtained in a yield of 1.2 g (52% of theory) as a colourless solid. Thissolid was a mixture of the product and the double Boc protectedcompound. The mixture was used for the next step without furtherpurification.

Step b1-(3-amino-2-chloropyridin-4-yl)-3-morpholin-4-yl-propane-1,3-dione

Under argon and at room temperature, 6.76 ml (6.76 mmol) of lithiumbis(trimethylsilyl)amide were added dropwise to a solution of 484 μl(4.19 mmol) of N-acetylmorpholine and 1.2 g (4.2 mmol) of methyl3-tert-butoxycarbonylamino-2-chloroisonicotinate in 10 ml of drytetrahydrofuran. The mixture was stirred at room temperature for 6 h.For work-up, the reaction mixture was adjusted to pH=1 using 2Nhydrochloric acid and stirred at room temperature for 16 h. LC-MS showedcomplete removal of the protective group. The mixture was extractedthree times with in each case 50 ml of dichloromethane. The combinedorganic phases were dried with sodium sulphate and then concentrated todryness. In this manner,1-(3-amino-2-chloropyridin-4-yl)-3-morpholin-4-yl-propane-1,3-dione wasobtained in a yield of 680 mg (57% of theory) as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ[ppm]=3.49-3.52 (2H), 3.64-3.74 (6H), 4.08 (s, 2H),6.73 (s, 2H), 7.57 (d, 1H), 7.75 (d, 1H).

Step c1-{3-amino-2-[2-(4-methoxybenzyl)-2H-pyrazol-3-yl]pyridin-4-yl}-3-(morpholin-4-yl)propane-1,3-dione

Under argon, 207 mg (0.66 mmol) of1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)-1H-pyrazole,195 mg (0.6 mmol) of caesium carbonate, 95 mg (0.33 mmol) of1-(3-amino-2-chloropyridin-4-yl)-3-morpholin-4-ylpropane-1,3-dione and20 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) in 2.5 ml of dioxane were stirred in a microwavevessel at 100° C. for 2 h. Without work-up, the residue was purified bycolumn chromatography [Puriflash silica gel 60 (25 g, 30 μm); ethylacetate/methanol 1:1, (200 ml)]. In this manner,1-{3-amino-2-[2-(4-methoxybenzyl)-2H-pyrazol-3-yl]pyridin-4-yl}-3-(morpholin-4-yl)propane-1,3-dionewas obtained in a yield of 38 mg (26% of theory) as a light-yellow oil.¹H NMR (400 MHz, CDCl₃): δ[ppm]=3.48-3.51 (2H), 3.64-3.68 (6H), 4.09(2H), 5.37 (2H), 6.43 (2H), 6.55 (1H), 6.69-6.73 (2H), 6.95-6.97 (2H),7.58-7.62 (2H), 8.09 (1H).

Step d 4-chloro-2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

Under argon, 45 mg (0.1 mmol) of1-{3-amino-2-[2-(4-methoxybenzyl)-2H-pyrazol-3-yl]pyridin-4-yl}-3-(morpholin-4-yl)propane-1,3-dioneand 500 μl (5.36 mmol) of phosphorus oxychloride were stirred at 120° C.for 3 h. Without work-up, the residue was purified by columnchromatography [Puriflash silica gel 60 (12 g, 30 μm); ethylacetate/methanol 1:1, (100 ml)]. In this manner,4-chloro-2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine wasobtained in a yield of 25 mg (79% of theory) as a yellow solid. ¹H NMR(400 MHz, DMSO): δ [ppm]=3.69-3.79 (8H), 7.36 (1H), 7.64 (1H), 7.78(1H), 7.85 (1H), 8.45 (1H). LCMS (method 1): m/z: [M+H]⁺=316.3,R_(t)=3.0 min.

Example 632-[(3R)-3-methylmorpholin-4-yl]-4-(methylsulfanyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-Chloro-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(50 mg, 0.12 mmol, 1 eq.) was solubilised in DMF (3 mL). Sodiummethanethiolate (8.5 mg, 0.12 mmol, 1 eq.) was added and the reactionwas stirred at 50° C. for 2 h. Sat. NH₄Cl was added to the mixture andthe aqueous phase was extracted 3 times with CH₂Cl₂. The organic phasewas dried (silicon filter) and concentrated under reduced pressure. Thecrude mixture was purified by preparative HPLC (H₂O(HCOOH)/CH₃CN: 56:44to 36:64). The desired product was obtained in 75% yield. ¹H-NMR (400MHz, DMSO-d₆): δ [ppm]: 1.28 (3H), 2.69 (3H), 3.34 (1H), 3.56 (1H), 3.71(1H), 3.83 (1H), 4.05 (1H), 4.17 (1H), 4.61-4.68 (1H), 7.08 (1H), 7.37(1H), 7.61 (1H), 7.66 (1H), 8.36 (1H), 13.36 (br. s, 1H).

Example 64N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1,4λ⁴-oxathian-4-imine4-oxide Step aN-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)-1,4λ⁴-oxathian-4-imine4-oxide

Under argon, 8 mg (0.014 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75mg (0.142 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 25 mg (0.19 mmol) 1,4λ⁴-oxathian-4-imine4-oxide and 69 mg (0.21 mmol) caesium carbonate in 0.67 ml toluene. Themixture was stirred at 110° C. for 3 hours. After cooling, the reactionmixture was diluted with ethyl acetate/THF and washed with an aqueoussolution of sodium chloride. The organic phase was filtered using aWhatman filter and concentrated to give 113 mg crude product that wasused without further purification.

Step bN-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1,4λ⁴-oxathian-4-imine4-oxide

0.25 ml (0.51 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 113 mg crudeN-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)-1,4λ⁴-oxathian-4-imine4-oxide in 1.0 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 23 mg (0.05 mmol) of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.43 (3H), 3.43 (2H),3.51 (1H), 3.61 (2H), 3.70 (1H), 3.85 (1H), 3.92 (2H), 4.14 (3H), 4.30(2H), 4.38 (1H), 6.97 (1H), 7.26 (1H), 7.72 (1H), 7.89 (1H), 8.43 (1H).

Example 654-{[dimethyl(oxido)-λ⁶-sulfanylidene]amino}-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-{[dimethyl(oxido)-λ⁶-sulfanylidene]amino}-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 11 mg (0.019 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 9 mg (0.010 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 100mg (0.20 mmol)2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 24 mg (0.26 mmol) S,S-dimethylsulfoximin and95 mg (0.29 mmol) caesium carbonate in 0.92 ml toluene. The mixture wasstirred at 110° C. for 3 hours. After cooling, the reaction mixture wasdiluted with ethyl acetate/THF and washed with an aqueous solution ofsodium chloride. The organic phase was filtered using a Whatman filterand concentrated to give 136 mg crude product that was used withoutfurther purification.

Step b4-{[dimethyl(oxido)-λ⁶-sulfanylidene]amino}-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.34 ml (0.68 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 135 mg crude4-{[dimethyl(oxido)-λ⁶-sulfanylidene]amino}-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.4 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preperative HPLC(Autopurifier: acidic conditions) to give 23 mg (0.06 mmol) of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ [ppm]=3.39 (6H), 3.70 (4H),3.94 (4H), 6.93 (1H), 7.25 (1H), 7.72 (1H), 7.82 (1H), 8.43 (1H).

Example 662-[(3R)-3-methylmorpholin-4-yl]-4-(piperazin-1-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(piperazin-1-yl)-8-[1-(tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, a mixture of 75 mg (0.14 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, and 42 mg (0.48 mmol) piperazine in 0.21 mlacetonitrile was stirred at 70° C. for 90 minutes. After cooling, thereaction mixture was diluted with ethyl acetate and washed with anaqueous solution of sodium chloride. The organic phase was filteredusing a Whatman filter and concentrated to give 91 mg crude product thatwas used without further purification.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(piperazin-1-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.30 ml (0.60 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 120 mg crude2-[(3R)-3-methylmorpholin-4-yl]-4-(piperazin-1-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 1.2 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 27 mg (0.07 mmol) of thedesired product. ¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.44 (3H), 3.21 (8H),3.54 (1H), 3.73 (1H), 3.87 (1H), 3.95 (2H), 4.18 (1H), 4.40 (1H), 6.56(1H), 7.27 (1H), 7.57 (1H), 7.71 (1H), 8.40 (1H).

Example 674-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineStep a4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine

96 mg (0.69 mmol) of potassium carbonate were added to a solution of 380mg (0.58 mmol) of 2-[(3S)-3-methylmorpholin-4-yl]-8-(2-tetrahydropyran-2-ylpyrazol-3-yl)-1,7-naphthyridin-4-ol and 0.12 ml (1.15mmol) of 2-iodopropane in 20 ml of acetonitrile. The suspension wasstirred in a microwave vessel at 70° C. for 16 h. Under reducedpressure, the mixture was concentrated to dryness. The residue was takenup in 50 ml of water and extracted four times with in each case 50 ml ofdichloromethane. The combined organic phases were dried over sodiumsulphate and then, under reduced pressure, concentrated to dryness. Theresidue was chromatographed [silica gel 60 (40 g, 50 μm); ethyl acetate100%]. 139 mg (55% of theory) of4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridinewere obtained as a beige solid. ¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.30(3H), 1.48 (m, 1H), 1.49 (6H), 1.56-1.77 (2H), 2.02-2.10 (2H), 2.52(1H), 3.27 (1H), 3.44 (1H), 3.57 (1H); 3.70-3.82 (2H), 3.93-4.16 (3H),4.35 (1H), 4.78 (1H), 6.02 (1H), 6.32 (1H); 6.94 (1H), 7.67 (1H), 7.78(1H), 6.39 (1H). LC-MS (method 1): R_(t)=3.75 min; MS (ESI/APCIpos)m/z=438.3 [M+H]⁺.

Step b4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridine

127 mg (0.29 mmol) of (3S)-4-[4-isopropoxy-8-(2-tetrahydropyran-2-ylpyrazol-3-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholinewere dissolved in 10 ml of methanol, 1.5 ml of 2N hydrochloric acid (3mmol) were added and the mixture was stirred at room temperature for 1h. After 1 h, the LC/MS showed complete removal of the protective group.The methanol was removed under reduced pressure. Saturated sodiumbicarbonate solution (pH=7) was added to the residue. The aqueous phasewas extracted five times with in each case 10 ml of dichloromethane. Thecombined organic phases were dried over sodium sulphate and then, underreduced pressure, concentrated to dryness. This gave 89 mg (87% oftheory) of4-isopropoxy-2-((S)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]naphthyridineas a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ [ppm]=1.41 (3H), 1.50(6H), 3.50 (1H), 3.70 (1H), 3.85 (1H), 3.90 (1H), 3.92 (1H), 4.15 (1H),4.34 (1H), 4.80 (1H), 6.39 (1H), 7.24 (1H), 7.69 (1H), 7.73 (1H), 8.39(1H), 13.18 (1H). ¹³C NMR (101 MHz, CDCl₃): δ [ppm]=13.4, 21.6, 21.7,40.8, 48.9, 66.8, 71.0, 71.7, 91.9, 105.7, 114.3, 123.4, 139.9, 140.0,140.8, 143.2, 143.9, 158.9, 161.0. LC-MS (method 1): R_(t)=2.90 min; MS(ESI/APCIpos) m/z=354.3 [M+H]⁺.

Example 682-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(1H-pyrrol-3-yl)-1,7-naphthyridine

Under argon, 13 mg (0.016 mmol)[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were addedto a mixture of 50 mg (0.16 mmol)8-chloro-2-(morpholin-4-yl)-4-(propan-2-yloxy)-1,7-naphthyridine and 34mg (0.18 mmol)3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole in 1.5 mlacetonitrile and 1.5 ml 2M aqueous solution of potassium carbonate. Themixture was stirred in a at 130° C. in a microwave oven for 10 minutes.After cooling, DCM was added and the mixture was filtered using aWhatman filter. The organic phase was concentrated and the residue waspurified by preparative HPLC separation (Autopurifier: acidicconditions) to give 5 mg (0.01 mmol) of the desired product. ¹H-NMR (400MHz, DMSO-d6): δ [ppm]=1.38 (6H), 3.67 (4H), 3.78 (4H), 5.02 (1H), 6.78(2H), 6.98 (1H), 7.44 (1H), 8.07 (1H), 8.17 (1H), 10.94 (1H).

Example 694-(1-ethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-ethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)(1-ethyl-1H-pyrazol-5-yl)boronic acid, 15 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2 ml MeCN and 1 ml water was degased with argon. Underargon, the reaction mixture was stirred at 130° C. for 10 min in amicrowave reactor. After cooling the reaction mixture was diluted withsaturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b4-(1-ethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 104 mg of crude4-(1-ethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2 ml of methanol and 0.2 ml of 2N hydrochloric acid wasstirred for 1 h at room temperature. The reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were dried over magnesiumsulphate and then concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.03mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.22 (3H), 1.30 (3H), 3.35-3.40 (1H),3.58 (1H), 3.72 (1H), 3.82 (1H), 3.99 (2H), 4.03-4.09 (1H), 4.23 (1H),4.64 (1H), 6.55 (1H), 7.19 (1H), 7.44 (1H), 7.58 (1H), 7.65 (1H), 7.70(1H), 8.35 (1H), 13.45 (1H).

Example 704-(1-methyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-methyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 79 mg (0.38 mmol)1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole,15 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2 ml MeCN and 1 ml water was degased with argon. Underargon, the reaction mixture was stirred at 130° C. for 10 min in amicrowave reactor. After cooling the reaction mixture was diluted withsaturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-(1-methyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 99 mg of crude4-(1-methyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2 ml of methanol and 0.2 ml of 2N hydrochloric acid wasstirred for 1 h at room temperature. The reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were dried over magnesiumsulphate and then concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 3.50-3.65 (4H), 3.72 (1H),3.83 (1H), 4.06 (1H), 4.23 (1H), 4.54-4.71 (1H), 7.24 (1H), 7.43 (2H),7.51 (1H), 7.65 (1H), 7.93 (1H), 8.36 (1H), 13.43 (1H).

Example 712-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]anilineStep a2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}aniline

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 52 mg (0.38 mmol) (2-aminophenyl)boronicacid, 15 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 2 h. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]aniline

A solution of 163 mg of crude2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}anilinefrom step a in 7.8 ml of methanol and 0.35 ml of 2N hydrochloric acidwas stirred for 90 min at room temperature. The reaction mixture wastreated with 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 17 mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.45-3.64 (1H), 3.71 (1H),3.82 (1H), 3.91-4.12 (1H), 4.21 (1H), 4.61 (1H), 4.84 (2H), 6.70 (1H),6.82 (1H), 7.02 (1H), 7.08-7.27 (2H), 7.35 (1H), 7.44 (1H), 7.64 (1H),8.28 (1H), 13.28 (1H).

Example 724-(2,3-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(2,3-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 60 mg (0.38 mmol) (2,3-difluorophenyl)boronicacid, 15 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 2 h. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(2,3-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 133 mg of crude4-(2,3-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 6.1 ml of methanol and 0.27 ml of 2N hydrochloric acidwas stirred for 90 min at room temperature. The reaction mixture wastreated with 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 20 mg (0.05 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.39 (1H), 3.58 (1H), 3.72(1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.64 (1H), 7.22 (1H), 7.35-7.52(3H), 7.52-7.75 (4H), 8.33 (1H), 13.09 (1H).

Example 73

4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Step a4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 84 mg (0.28 mmol)2-methyl-6-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,12 mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 185 mg (0.57 mmol) of caesiumcarbonate in 1.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 h. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 152 mg of crude4-[2-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.3 ml of methanol and 0.3 ml of 2N hydrochloric acid wasstirred for 1 h at room temperature. The reaction mixture was treatedwith 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 36 mg (0.08 mmol) of the desired product. ¹H-NMR(400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 2.36 (3H), 3.33-3.44 (4H),3.46-3.63 (1H), 3.66-3.76 (1H), 3.76-3.88 (1H), 4.04 (1H), 4.21 (1H),4.55-4.64 (1H), 6.99 (1H), 7.43 (1H), 7.51-7.61 (1H), 7.64 (1H),7.97-8.15 (2H), 8.29 (1H), 13.41 (1H).

Example 744-[2-fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-4-(methylsulfanyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 106 mg (0.57 mmol)[2-fluoro-4-(methylsulfanyl)phenyl]boronic acid, 23 mg (0.028 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 371 mg (1.14 mmol) of caesiumcarbonate in 2.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 150 min. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated. Theresidue was purified by flash chromatography (gradient Hex/EtOAc 9/1 to100% EtOAc) to give 96 mg (0.18 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.21 (3H), 1.35-1.56 (3H), 1.87-2.08(2H), 2.29-2.43 (1H), 2.58 (3H), 3.08-3.26 (2H), 3.39-3.58 (1H),3.58-3.66 (1H), 3.66-3.79 (2H), 3.95 (1H), 4.16 (1H), 4.47-4.58 (1H),6.10 (1H), 6.94 (1H), 7.23 (1H), 7.26-7.32 (1H), 7.35 (1H), 7.43 (1H),7.48 (1H), 7.62 (1H), 8.34 (1H).

Step b4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4-methylmorpholineN-oxide were added to a stirred solution of 92 mg (0.18 mmol) of4-[2-fluoro-4-(methylsulfanyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 2 ml DCM and 2 ml MeCN at 0°. After 4 h, additional 2.7 mg (0.009mmol) TPAP was added and the ice bath removed. After 14 h at Rt,additional 2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol)4-methylmorpholine N-oxide were added and the mixture was stirred atroom temperature. After 18 h at Rt, additional 2.7 mg (0.009 mmol) TPAPand 20.7 mg (0.18 mmol) 4-methylmorpholine N-oxide were added and themixture was stirred at room temperature. After 16 h at Rt, additional2.7 mg (0.009 mmol) TPAP and 20.7 mg (0.18 mmol) 4-methylmorpholineN-oxide were added and the mixture was stirred at room temperature. Thereaction was filtered using a Whatman filter and concentrated to givethe crude product that was used without further purification in the nextstep.

Step c4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 134 mg of crude4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step b in 5.4 ml of methanol and 0.25 ml of 2N hydrochloric acidwas stirred for 90 min at room temperature. The reaction mixture wastreated with 10 ml of a saturated aqueous sodium bicarboante solutionand extracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 23 mg (0.05 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 3.33-3.42 (4H), 3.50-3.61(1H), 3.66-3.76 (1H), 3.81 (1H), 3.95-4.09 (1H), 4.21 (1H), 4.54-4.71(1H), 7.15 (1H), 7.42 (1H), 7.56-7.70 (2H), 7.87 (1H), 7.98 (1H), 8.03(1H), 8.31 (1H), 13.40 (1H).

Example 754-fluoro-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]anilineStep a4-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}aniline

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 58 mg (0.38 mmol)(2-amino-5-fluorophenyl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-fluoro-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]aniline

A solution of 59 mg of crude4-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}anilinefrom step a in 3.0 ml of methanol and 0.12 ml of 2N hydrochloric acidwas stirred for 3 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 22mg (0.05 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.57 (1H), 3.65-3.76 (1H),3.76-3.88 (1H), 4.05 (1H), 4.22 (1H), 4.62 (1H), 4.74 (2H), 6.81 (1H),6.94 (1H), 7.07 (1H), 7.14 (1H), 7.39 (1H), 7.44 (1H), 7.59-7.73 (m,1H), 8.29 (1H), 13.42 (1H).

Example 764-(1-benzyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-benzyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.19 mmol)1-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of cesiumcarbonate was degased with argon. Under argon, the reaction mixture wasstirred at 110° C. for 90 minutes. After cooling the reaction mixturewas diluted with saturated aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-(1-benzyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 170 mg of crude4-(1-benzyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.32 ml of 2N hydrochloric acidwas stirred for 3 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 5mg (0.01 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.17 (3H), 3.22 (1H), 3.51 (1H), 3.65(1H), 3.76 (1H), 3.90-4.07 (2H), 4.32 (1H), 5.24 (2H), 6.86 (2H),7.11-7.24 (4H), 7.26 (1H), 7.34 (1H), 7.38 (1H), 7.63 (1H), 8.13 (1H),8.29 (1H), 13.40 (1H).

Example 774-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol) (2-fluorophenyl)boronicacid, 15 mg (0.02 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 2 h. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 126 mg of4-(2-fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 6 ml of methanol and 0.27 ml of 2N hydrochloric acid wasstirred for 90 min at room temperature. The reaction mixture was treatedwith 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 16 mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.39 (1H), 3.58 (1H),3.64-3.77 (1H), 3.82 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.15 (1H),7.39-7.69 (7H), 8.32 (1H), 13.33 (1H).

Example 782-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-1,3-thiazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-1,3-thiazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 85 mg (0.38 mmol)2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 105 mg (0.76 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-1,3-thiazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 183 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-1,3-thiazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.8 ml of methanol and 0.44 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 14mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 2.79 (3H), 3.57 (1H), 3.71(1H), 3.83 (1H), 4.05 (1H), 4.21 (1H), 4.56-4.71 (1H), 7.40 (1H), 7.55(1H), 7.65 (1H), 7.73 (1H), 8.07 (1H), 8.39 (1H), 13.41 (1H).

Example 794-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 84 mg (0.28 mmol)4-methyl-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,11 mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 185 mg (0.56 mmol) of caesiumcarbonate in 1.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 h. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 152 mg of4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.3 ml of methanol and 0.32 ml of 2N hydrochloric acidwas stirred for 60 min at room temperature. The reaction mixture wastreated with 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 33 mg (0.07 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 2.23 (3H), 3.35 (4H), 3.57(1H), 3.65-3.76 (1H), 3.76-3.89 (1H), 4.04 (1H), 4.14-4.32 (1H), 4.60(1H), 6.98 (1H), 7.43 (1H), 7.57 (1H), 7.64 (1H), 8.17 (1H), 8.28 (1H),8.68 (1H), 13.41 (1H).

Example 804-(1-cyclopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-cyclopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 57 mg (0.38 mmol)(1-cyclopropyl-1H-pyrazol-5-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 1 h. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-(1-cyclopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 96 mg of crude4-(1-cyclopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.0 ml of methanol and 0.20 ml of 2N hydrochloric acidwas stirred for 3 h at room temperature. The reaction mixture wastreated with 2 ml of a saturated aqueous sodium bicarboante solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 6 mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.74-0.83 (2H), 0.91-1.02 (2H), 1.30(3H), 3.39 (1H), 3.52-3.64 (2H), 3.73 (1H), 3.83 (1H), 4.06 (1H), 4.23(1H), 4.60-4.71 (1H), 6.59 (1H), 7.28 (1H), 7.43 (1H), 7.53-7.79 (3H),8.36 (1H), 13.01 (1H).

Example 814-[2-fluoro-4-(piperazin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-4-(piperazin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 85 mg (0.38 mmol)[2-fluoro-4-(piperazin-1-yl)phenyl]boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-[2-fluoro-4-(piperazin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 106 mg of crude4-[2-fluoro-4-(piperazin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.38 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: acidic conditions) to give20 mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 2.78-3.01 (m, 4H),3.20-3.43 (m, 5H), 3.57 (1H), 3.72 (1H), 3.82 (1H), 4.04 (1H), 4.20(1H), 4.62 (1H), 6.81-7.03 (2H), 7.25 (1H), 7.30-7.49 (3H), 7.65 (1H),8.25 (1H), 8.32 (1H).

Example 822-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 159 mg (0.97 mmol)1-(methylsulfonyl)piperazine in 0.42 ml of MeCN was stirred at 70° C.for 8 h under argon. After cooling the reaction mixture was diluted withethyl acetate and THF and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 267 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-[4-(methylsulfonyl)piperazin-1-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.3 ml of methanol and 0.57 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 55 mg (0.12 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27 (3H), 3.00 (3H), 3.18-3.31 (5H),3.38-3.49 (4H), 3.55 (1H), 3.70 (1H), 3.83 (1H), 4.05 (1H), 4.13 (1H),4.53-4.64 (1H), 6.84 (1H), 7.35 (1H), 7.53-7.71 (2H), 8.33 (1H), 13.21(1H).

Example 83N-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amineStep aN-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-amine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 98 mg (0.97 mmol)N,2,2-trimethylpropan-1-amine in 0.42 ml of MeCN was stirred at 70° C.for 7 h under argon. After cooling the reaction mixture was diluted withethyl acetate and THF and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step bN-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine

A solution of 205 mg of crudeN-(2,2-dimethylpropyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-aminefrom step a in 2.0 ml of methanol and 0.50 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 47 mg (0.12 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.90 (9H), 1.23 (3H), 3.09 (3H),3.16-3.31 (2H), 3.36-3.42 (1H), 3.56 (1H), 3.63-3.78 (1H), 3.82 (1H),3.92-4.18 (2H), 4.49-4.61 (1H), 6.99 (1H), 7.34 (1H), 7.60 (1H), 7.73(1H), 8.30 (1H), 13.36 (1H).

Example 84(1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}piperidin-4-yl)methanolStep a(1-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperidin-4-yl)methanol

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 111 mg (0.97 mmol) piperidin-4-ylmethanolin 0.42 ml of MeCN was stirred at 70° C. for 3 h under argon. Aftercooling the reaction mixture was diluted with ethyl acetate and THF andwashed with saturated aqueous sodium chloride solution. The organicphase was filtered using a Whatman filter and then concentrated to givethe crude product that was used without further purification in the nextstep.

Step b(1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}piperidin-4-yl)methanol

A solution of 345 mg of crude(1-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperidin-4-yl)methanolfrom step a in 3.2 ml of methanol and 0.81 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 37 mg (0.09 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.26 (3H), 1.38-1.55 (2H), 1.55-1.71(1H), 1.76-1.96 (2H), 2.71-2.93 (2H), 3.22-3.31 (1H), 3.36-3.43 (2H),3.43-3.61 (3H), 3.70 (1H), 3.82 (1H), 4.03 (1H), 4.11 (1H), 4.51-4.62(2H), 6.74 (1H), 7.34 (1H), 7.56 (1H), 7.61 (1H), 8.31 (1H), 13.33 (1H).

Example 85N-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amineStep aN-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-amine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 69 mg (0.97 mmol)N-methylcyclopropanaminein 0.42 ml of MeCN was stirred at 70° C. for 7 h under argon. Aftercooling the reaction mixture was diluted with ethyl acetate and THF andwashed with saturated aqueous sodium chloride solution. The organicphase was filtered using a Whatman filter and then concentrated to givethe crude product that was used without further purification in the nextstep.

Step bN-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine

A solution of 188 mg of crudeN-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-aminefrom step a in 1.9 ml of methanol and 0.48 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 45 mg (0.12 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.34-0.56 (2H), 0.75-0.89 (2H), 1.27(3H), 2.78-2.89 (1H), 3.08 (3H), 3.23-3.32 (1H), 3.56 (1H), 3.66-3.76(1H), 3.83 (1H), 3.99-4.14 (2H), 4.46-4.58 (1H), 6.86 (1H), 7.33 (1H),7.60 (1H), 7.65 (1H), 8.25 (1H), 13.36 (1H).

Example 864-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 119 mg (0.97 mmol)5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine in 0.42 ml of MeCN was stirredat 70° C. for 48 h under argon. After cooling the reaction mixture wasdiluted with ethyl acetate and THF and washed with saturated aqueoussodium chloride solution. The organic phase was filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 106 mg of crude4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.0 ml of methanol and 0.21 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 6 mg (0.01 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.28 (3H), 3.55 (1H), 3.61-3.75 (3H),3.83 (1H), 4.05 (1H), 4.19 (1H), 4.25-4.36 (2H), 4.41-4.52 (2H), 4.62(1H), 6.91 (1H), 6.96 (1H), 7.22 (1H), 7.36 (1H), 7.62 (1H), 7.68 (1H),8.33 (1H), 13.38 (1H).

Example 87N-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amineStep aN-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-amine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 121 mg (0.97 mmol)4-fluoro-N-methylaniline in 0.42 ml of MeCN was stirred at 70° C. for 3h under argon. After cooling the reaction mixture was diluted with ethylacetate and THF and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step bN-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine

A solution of 273 mg of crudeN-(4-fluorophenyl)-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-aminefrom step a in 2.5 ml of methanol and 0.63 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate/THF (1:1) (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to dryness. Theresidue was purified by preparative HPLC (Autopurifier: basicconditions) to give 54 mg (0.13 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 3.45 (3H), 3.58 (1H), 3.73(1H), 3.84 (1H), 4.06 (1H), 4.16 (1H), 4.54-4.66 (1H), 6.95-7.02 (2H),7.03-7.15 (4H), 7.36 (1H), 7.62 (1H), 8.08 (1H), 13.26 (1H).

Example 882-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.10 g, 0.19 mmol) was solubilised in dioxane (1 ml).2-Methyl-5-pyridinylboronic acid (52 mg, 0.38 mmol) was added in oneportion followed by addition of caesium carbonate (0.25 g, 0.76 mmol)and PdCl₂(dppf) in complex with dichloromethane (31 mg, 0.038 mmol). Thereaction was heated for 4 hours in a sealed tube at 110° C. The reactionwas then cooled to rt and filtered. The solid was washed with ethylacetate and the filtrate was concentrated under reduced pressure. Thecrude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in dichloromethane and3N hydrochloric acid was added. The mixture was stirred overnight at rtand then quenched with a saturated aqueous solution of sodium hydrogencarbonate. The aqueous phase was extracted three times withdichloromethane. The organic phase was dried, filtered and concentratedunder reduced pressure. The title compound was obtained in 53% yield (39mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 2.59 (s, 3H), 3.35-3.42(m, 1H), 3.56 (t, 1H), 3.71 (d, 1H), 3.82 (d, 1H), 4.05 (d, 1H), 4.23(d, 1H), 4.61-4.71 (m, 1H), 7.38 (d, 1H), 7.43 (s, 1H), 7.47 (d, 2H),7.63 (s, 1H), 7.92 (dd, 1H), 8.32 (d, 1H), 8.64 (d, 1H), 13.43 (s, 1H).

Example 894-(2-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.25 g, 0.47 mmol) was solubilised in dioxane (2.5 ml).(2-Fluoropyridin-3-yl)boronic acid (0.20 g, 1.4 mmol) was added in oneportion followed by addition of caesium carbonate (0.62 g, 1.90 mmol)and PdCl₂(dppf) in complex with dichloromethane (77 mg, 0.094 mmol). Thereaction was heated for 4 hours in a sealed tube at 110° C. The reactionwas then cooled to rt and filtered. The solid was washed withdichloromethane and the filtrate was concentrated under reducedpressure. The crude material was purified by flash column chromatography(hexane/ethyl acetate/ethanol mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (3 ml) and3N hydrochloric acid (10 ml) was added. The mixture was stirred for 2hours rt and then basified with a 3M sodium hydroxide solution. Thesuspension was filtered and washed with water. The solid was dried underreduced pressure at 60° C. The title compound was obtained in 90% yield(109 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 3.29-3.41 (m, 1H),3.51-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.78-3.86 (m, 1H), 4.00-4.09 (m,1H), 4.17-4.26 (m, 1H), 4.59-4.68 (m, 1H), 7.17 (dd, 1H), 7.43 (s, 1H),7.58-7.68 (m, 3H), 8.14-8.22 (m, 1H), 8.32 (d, 1H), 8.44-8.48 (m, 1H),13.43 (br. s, 1H).

Example 904-(2-fluoro-4-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.10 g, 0.19 mmol) was solubilised in dioxane (1 ml).(2-Fluoro-4-methylpyridin-3-yl)boronic acid (61 mg, 0.38 mmol) was addedin one portion followed by addition of caesium carbonate (0.25 g, 0.76mmol) and PdCl₂(dppf) in complex with dichloromethane (31 mg, 0.038mmol). The reaction was heated for 4 hours in a sealed tube at 110° C.The reaction was then cooled to rt and filtered. The filtrate wasconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (acetonitrile/water/formic acid mixture). The combinedfractions were concentrated under reduced pressure, solubilised indichloromethane and washed with a saturated solution of sodium hydrogencarbonate. The organic phase was dried (silicon filter) and concentratedunder reduced pressure. The title compound was obtained in 47% yield (36mg).

¹H-NMR (400 MHz, CHLOROFORM-d): δ [ppm]=1.47 (dd, 3H), 2.16 (d, 3H),3.58 (td, 1H), 3.70-3.78 (m, 1H), 3.90-3.95 (m, 2H), 4.01-4.09 (m, 1H),4.19 (dd, 1H), 4.37-4.46 (m, 1H), 6.94 (d, 1H), 7.13 (d, 1H), 7.26 (d,1H), 7.32-7.35 (m, 1H), 7.74 (d, 1H), 8.27 (d, 1H), 8.37 (d, 1H).

Example 912-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrrol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.10 g, 0.19 mmol1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (79mg, 0.38 mmol), aq. potassium carbonate (0.29 ml, 2 M) and PdCl₂(PPh₃)₂(13 mg, 0.019 mmol) were solubilised in dimethoxyethane (5 ml). Thereaction mixture was stirred for 10 minutes at 130° C. under microwaveirradiation. After cooling to rt, the reaction mixture was dried byfiltration and the filtrate was concentrated under reduced pressure. Thecrude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in dichloromethane andwashed with a saturated solution of sodium hydrogen carbonate. Theorganic phase was dried (silicon filter) and concentrated under reducedpressure. The title compound was obtained in 53% yield (39 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 3.28-3.39 (m, 1H),3.52-3.62 (m, 4H), 3.68-3.76 (m, 1H), 3.78-3.86 (m, 1H), 4.00-4.09 (m,1H), 4.18-4.26 (m, 1H), 4.59-4.68 (m, 1H), 6.22-6.28 (m, 1H), 6.35 (dd,1H), 7.07 (dd, 1H), 7.41 (s, 2H), 7.48 (d, 1H), 7.64 (br. s, 1H), 8.34(d, 1H), 13.41 (br. s, 1H).

Example 924-(6-fluoro-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2ml). (6-Fluoro-5-methylpyridin-3-yl)boronic acid (44 mg, 0.28 mmol) wasadded in one portion followed by addition of caesium carbonate (0.19 g,0.59 mmol) and PdCl₂(dppf) in complex with dichloromethane (11 mg, 0.014mmol). The reaction was heated for 4 hours in a sealed tube at 110° C.The reaction was then cooled to rt and filtered. The filtrate wasconcentrated under reduced pressure. The crude material was purified byflash column chromatography (hexane/ethyl acetate mixture). The combinedfractions were concentrated under reduced pressure, solubilised inmethanol (1.5 ml) and 3N hydrochloric acid (1.6 ml) was added. Themixture was stirred overnight at rt and then basified with a 3M sodiumhydroxide solution. The suspension was filtered and washed with water.The solid was purified by preparative HPLC (acetonitrile/water/formicacid mixture). The title compound was obtained in 20% yield (11 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (dd, 3H), 2.12 (s, 3H),3.36-3.39 (m, 1H), 3.52-3.63 (m, 1H), 3.68-3.76 (m, 1H), 3.78-3.85 (m,1H), 4.01-4.09 (m, 1H), 4.18-4.27 (m, 1H), 4.57-4.66 (m, 1H), 7.00 (dd,1H), 7.33 (s, 1H), 7.40-7.45 (m, 1H), 7.51 (d, 1H), 7.65 (d, 1H), 8.17(d, 1H), 8.29 (d, 1H), 13.42 (br. s, 1H).

Example 934-(2-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml)under argon. (2-Fluoro-6-methylpyridin-3-yl)boronic acid (44 mg, 0.28mmol) was added in one portion followed by addition of caesium carbonate(0.19 g, 0.59 mmol) and PdCl₂(dppf) in complex with dichloromethane (11mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at110° C. The reaction was then cooled to rt and filtered. The filtratewas concentrated under reduced pressure. The crude material was purifiedby flash column chromatography (hexane/ethyl acetate mixture). Thecombined fractions were concentrated under reduced pressure, solubilisedin methanol (1 ml) and 3N hydrochloric acid (1 ml) was added. Themixture was stirred overnight at rt and then basified with a 3M sodiumhydroxide solution. The suspension was filtered and washed with water.The solid was purified by preparative HPLC (acetonitrile/water/formicacid mixture). The title compound was obtained in 54% yield (19 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 2.56 (s, 3H), 3.36-3.40(m, 1H), 3.52-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.79-3.86 (m, 1H),4.00-4.07 (m, 1H), 4.17-4.24 (m, 1H), 4.58-4.66 (m, 1H), 7.18 (dd, 1H),7.41 (d, 1H), 7.46 (dd, 1H), 7.58 (s, 1H), 7.65 (d, 1H), 8.04 (dd, 1H),8.32 (d, 1H), 13.41 (br. s, 1H).

Example 944-(6-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml)under argon. (6-Fluoropyridin-3-yl)boronic acid (40 mg, 0.28 mmol) wasadded in one portion followed by addition of caesium carbonate (0.19 g,0.59 mmol) and PdCl₂(dppf) in complex with dichloromethane (11 mg, 0.014mmol). The reaction was heated for 4 hours in a sealed tube at 110° C.The reaction was then cooled to rt and filtered. The filtrate wasconcentrated under reduced pressure. The crude material was purified byflash column chromatography (hexane/ethyl acetate mixture). The combinedfractions were concentrated under reduced pressure, solubilised inmethanol (1.4 ml) and 3N hydrochloric acid (1.4 ml) was added. Themixture was stirred overnight at rt and then basified with a 3M sodiumhydroxide solution. The suspension was filtered and washed with water.The solid was purified by preparative HPLC (acetonitrile/water/formicacid mixture). The title compound was obtained in 10% yield (5 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 3.35-3.41 (m, 1H),3.52-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.79-3.86 (m, 1H), 4.01-4.09 (m,1H), 4.19-4.28 (m, 1H), 4.62-4.71 (m, 1H), 7.37 (d, 1H), 7.39-7.46 (m,2H), 7.55 (s, 1H), 7.62-7.68 (m, 1H), 8.21-8.29 (m, 1H), 8.34 (d, 1H),8.48 (d, 1H), 13.43 (br. s, 1H).

Example 954-(6-methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-(6-Fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(10 mg, 0.026 mmol) was solubilised in methanol (3 ml) and the mixturewas stirred overnight at 50° C. Sodium methoxide was then added to themixture (7.1 mg, 0.13 mmol) and the reaction was stirred for additional18 hours at 50° C. The reaction mixture was cooled to rt andconcentrated under reduced pressure. The crude material was purified bypreparative HPLC (acetonitrile/water/formic acid mixture) and the titlecompound was obtained in 59% yield (6.3 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 3.34-3.40 (m, 1H),3.50-3.62 (m, 1H), 3.68-3.75 (m, 1H), 3.79-3.86 (m, 1H), 3.96 (s, 3H),4.01-4.09 (m, 1H), 4.19-4.28 (m, 1H), 4.61-4.71 (m, 1H), 7.04 (d, 1H),7.42 (d, 2H), 7.47 (s, 1H), 7.64 (br. s, 1H), 7.96 (dd, 1H), 8.33 (d,1H), 8.40 (d, 1H), 13.41 (br. s, 1H).

Example 964-(6-methoxy-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-(6-fluoro-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(13 mg, 0.031 mmol) was solubilised in methanol (3 ml) and the mixturewas stirred overnight at 50° C. Sodium methoxide was then added to themixture (8.3 mg, 0.16 mmol) and the reaction was stirred for additional18 hours at 50° C. Sodium methoxide was again added (8.3 mg, 0.16 mmol)and the reaction was stirred for 24 hours at 50° C. The reaction mixturewas cooled to rt and concentrated under reduced pressure. The crudematerial was purified by preparative HPLC (acetonitrile/water/formicacid mixture) and the title compound was obtained in 93% yield (12 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (dd, 3H), 2.04 (s, 3H),3.34-3.40 (m, 1H), 3.52-3.63 (m, 1H), 3.68-3.76 (m, 1H), 3.77-3.85 (m,1H), 3.89-3.96 (m, 3H), 4.00-4.08 (m, 1H), 4.17-4.26 (m, 1H), 4.56-4.67(m, 1H), 6.91 (s, 1H), 7.00-7.06 (m, 1H), 7.39-7.47 (m, 2H), 7.64 (br.s, 1H), 8.07 (s, 1H), 8.29 (d, 1H), 13.41 (br. s, 1H).

Example 974-(6-fluoro-2-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol) was solubilised in dioxane (3.2 ml)under argon. (6-Fluoro-2-methylpyridin-3-yl)boronic acid (44 mg, 0.28mmol) was added in one portion followed by addition of caesium carbonate(0.19 g, 0.59 mmol) and PdCl₂(dppf) in complex with dichloromethane (11mg, 0.014 mmol). The reaction was heated for 4 hours in a sealed tube at110° C. The reaction was then cooled to rt and filtered. The filtratewas concentrated under reduced pressure. The crude material was purifiedby preparative HPLC (acetonitrile/water/formic acid mixture) followed byflash column chromatography (hexane/ethyl acetate mixture). The titlecompound was obtained in 68% yield (41 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (t, 3H), 2.21 (d, 3H), 3.28-3.39(m, 1H), 3.52-3.62 (m, 1H), 3.68-3.76 (m, 1H), 3.77-3.85 (m, 1H),4.00-4.08 (m, 1H), 4.17-4.27 (m, 1H), 4.56-4.66 (m, 1H), 7.02 (dd, 1H),7.21 (dd, 1H), 7.44 (br. s., 1H), 7.51 (d, 1H), 7.64 (br. s., 1H), 7.94(t, 1H), 8.29 (d, 1H), 13.43 (br. s, 1H).

Example 982-[(3R)-3-methylmorpholin-4-yl]-4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-18 (0.060 g, 0.14 mmol) was solubilised in dioxane (3.3 ml)under argon. [1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid(56 mg, 0.28 mmol) was added in one portion followed by addition ofcaesium carbonate (0.19 g, 0.58 mmol) and PdCl₂(dppf) in complex withdichloromethane (11 mg, 0.014 mmol). The reaction was heated for 4 hoursin a sealed tube at 110° C. The reaction was then cooled to rt andfiltered. The filtrate was concentrated under reduced pressure andpurified by flash column chromatography (hexane/ethyl acetate mixture)followed by preparative TLC (hexane/MTBE mixture). The combinedfractions were concentrated under reduced pressure, solubilised inmethanol (1 ml) and 3N hydrochloric acid (2 ml) was added. The mixturewas stirred overnight at rt and then basified with a 3M sodium hydroxidesolution. The suspension was filtered and washed with water. The solidwas dried under reduced pressure at 60° C. The title compound wasobtained in 6% yield (4 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 3.36-3.42 (m, 1H),3.52-3.62 (m, 1H), 3.68-3.75 (m, 1H), 3.79-3.87 (m, 4H), 4.01-4.09 (m,1H), 4.19-4.27 (m, 1H), 4.59-4.68 (m, 1H), 7.13 (s, 1H), 7.25 (d, 1H),7.43 (br. s, 1H), 7.65 (br. s, 1H), 7.72 (s, 1H), 8.36 (d, 1H), 13.45(br. s, 1H).

Example 992-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-2-thienyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol), (3-methylthiophen-2-yl)boronicacid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) andPdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) and3M hydrochloric acid (2 ml) was added. The reaction was stirredovernight at rt and then basified with a 3M sodium hydroxide solution.The suspension was filtered and washed with water. The solid was driedunder reduced pressure at 60° C. The title compound was obtained in 66%yield (38 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 2.09 (s, 3H), 3.28-3.39(m, 1H), 3.51-3.62 (m, 1H), 3.67-3.75 (m, 1H), 3.78-3.85 (m, 1H),3.99-4.08 (m, 1H), 4.15-4.25 (m, 1H), 4.58-4.67 (m, 1H), 7.16 (d, 1H),7.32 (d, 1H), 7.41 (d, 1H), 7.46 (s, 1H), 7.64 (d, 1H), 7.73 (d, 1H),8.34 (d, 1H), 13.35 (br. s, 1H).

Example 1002-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-2-thienyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol), (5-methylthiophen-2-yl)boronicacid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) andPdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) and3M hydrochloric acid (2 ml) was added. The reaction was stirredovernight at rt and then basified with a 3M sodium hydroxide solution.The suspension was filtered and washed with water. The solid was driedunder reduced pressure at 60° C. The title compound was obtained in 67%yield (39 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (d, 3H), 2.57 (d, 3H), 3.28-3.39(m, 1H), 3.51-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.78-3.85 (m, 1H),4.00-4.08 (m, 1H), 4.15-4.23 (m, 1H), 4.58-4.67 (m, 1H), 7.02 (dd, 1H),7.34-7.45 (m, 3H), 7.63 (s, 1H), 7.86 (d, 1H), 8.38 (d, 1H), 13.40 (br.s, 1H).

Example 1012-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-3-thienyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol), (4-methylthiophen-3-yl)boronicacid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) andPdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in dichloromethane (2ml) and 3M hydrochloric acid (2 ml) was added. The reaction was stirredovernight at rt and then basified with a 3M sodium hydroxide solutionand extracted three times with dichloromethane. The organic phase wasdried (silicon filter) and concentrated under reduced pressure. Thetitle compound was obtained in 76% yield (45 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 2.03 (d, 3H), 3.33 (s,1H), 3.51-3.62 (m, 1H), 3.67-3.75 (m, 1H), 3.77-3.84 (m, 1H), 4.00-4.08(m, 1H), 4.17-4.26 (m, 1H), 4.57-4.67 (m, 1H), 7.17 (d, 1H), 7.37-7.47(m, 3H), 7.64 (d, 1H), 7.68 (d, 1H), 8.31 (d, 1H), 13.40 (br. s, 1H).

Example 1024-(3-chloro-2-thienyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol), (3-chlorothiophen-2-yl)boronicacid (46 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) andPdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/ammonium hydroxyde). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) and3M hydrochloric acid (2 ml) was added. The reaction was stirredovernight at rt and then basified with a 3M sodium hydroxide solution.The suspension was filtered and washed with water. The solid was driedunder reduced pressure at 60° C. The title compound was obtained in 4%yield (2 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 3.34-3.39 (m, 1H),3.52-3.62 (m, 1H), 3.68-3.75 (m, 1H), 3.78-3.85 (m, 1H), 3.99-4.08 (m,1H), 4.16-4.25 (m, 1H), 4.58-4.67 (m, 1H), 7.28 (d, 1H), 7.35 (d, 1H),7.40 (s, 1H), 7.58 (s, 1H), 7.65 (s, 1H), 7.98 (d, 1H), 8.36 (d, 1H),13.41 (br. s, 1H).

Example 1032-[(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-3-thienyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.10 g, 0.19 mmol), 2-methylthiophene-3-boronic acidpinacol ester (85 mg, 0.38 mmol), aq. potassium carbonate (0.28 ml, 2 M)and PdCl₂(PPh₃)₂ (13 mg, 0.019 mmol) were solubilised in dimethoxyethane(5 ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) andconcentrated hydrochloric acid (1.5 ml) was added. The reaction wasstirred overnight at rt and then basified with a saturated solution ofsodium hydrogen carbonate and extracted three times withdichloromethane. The organic phase was dried (silicon filter) andconcentrated under reduced pressure. The title compound was obtained in48% yield (37 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.28 (d, 3H), 2.32 (s, 3H), 3.34-3.38(m, 1H), 3.51-3.62 (m, 1H), 3.66-3.75 (m, 1H), 3.79 (d, 1H), 4.00-4.08(m, 1H), 4.16-4.25 (m, 1H), 4.57-4.66 (m, 1H), 7.12 (d, 1H), 7.23 (d,1H), 7.40 (d, 2H), 7.53 (d, 1H), 7.63 (br. s., 1H), 8.31 (d, 1H), 13.41(br. s, 1H).

Example 1042-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrrolo[2,3-b]pyridine (69 mg, 0.28 mmol), aq. potassium carbonate(0.21 ml, 2 M) and PdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised indimethoxyethane (4 ml). The reaction mixture was stirred for 10 minutesat 130° C. under microwave irradiation. After cooling to rt, thereaction mixture was diluted with water and extracted withdichloromethane and the ethyl acetate. The combined organic phases weredried (silicon filter) and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC(acetonitrile/water/formic acid). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) andconcentrated hydrochloric acid (1.5 ml) was added. The reaction wasstirred overnight at rt and then basified with a saturated solution ofsodium hydrogen carbonate and extracted three times withdichloromethane. The organic phase was dried (silicon filter) andconcentrated under reduced pressure. The title compound was obtained in71% yield (43 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.31 (d, 3H), 3.35-3.42 (m, 1H), 3.57(t, 1H), 3.72 (d, 1H), 3.81 (d, 1H), 4.05 (d, 1H), 4.22 (d, 1H),4.58-4.67 (m, 1H), 6.13-6.18 (m, 1H), 7.22 (t, 2H), 7.46 (s, 1H), 7.54(s, 2H), 7.63-7.67 (m, 1H), 8.26 (d, 1H), 8.40 (d, 1H), 11.96 (br. s,1H), 13.44 (br. s, 1H).

Example 1054-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol), 3,5-dimethylisoxazole-4-boronicacid (40 mg, 0.28 mmol), aq. potassium carbonate (0.21 ml, 2 M) andPdCl₂(PPh₃)₂ (10 mg, 0.019 mmol) were solubilised in dimethoxyethane (4ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdiluted with water and filtered. The solid was purified by preparativeHPLC (acetonitrile/water/formic acid). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) andconcentrated hydrochloric acid (1.5 ml) was added. The reaction wasstirred overnight at rt and then basified with a saturated solution ofsodium hydrogen carbonate and extracted three times withdichloromethane. The organic phase was dried (silicon filter) andconcentrated under reduced pressure. The title compound was obtained in42% yield (24 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.29 (d, 3H), 2.12 (s, 3H), 2.32 (s,3H), 3.35-3.40 (m, 1H), 3.57 (t, 1H), 3.72 (d, 1H), 3.82 (d, 1H), 4.05(d, 1H), 4.22 (d, 1H), 4.61 (d, 1H), 7.21-7.28 (m, 1H), 7.42 (s, 1H),7.52 (s, 1H), 7.62-7.67 (m, 1H), 8.33 (d, 1H), 13.43 (br. s, 1H).

Example 1064-(3-chloro-2-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol),3-chloro-2-methoxypyridine-4-boronic acid (53 mg, 0.28 mmol), aq.potassium carbonate (0.21 ml, 2 M) and PdCl₂(PPh₃)₂ (10 mg, 0.019 mmol)were solubilised in dimethoxyethane (4 ml). The reaction mixture wasstirred for 10 minutes at 130° C. under microwave irradiation. Aftercooling to rt, the reaction mixture was diluted with water and filtered.The solid was purified by preparative HPLC (acetonitrile/water/formicacid). The combined fractions were concentrated under reduced pressure,solubilised in methanol (2 ml) and concentrated hydrochloric acid (1.5ml) was added. The reaction was stirred 2 hours at rt and then basifiedwith a saturated solution of sodium hydrogen carbonate and extractedthree times with dichloromethane. The organic phase was dried (siliconfilter) and concentrated under reduced pressure. The title compound wasobtained in 22% yield (14 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.25-1.33 (m, 3H), 3.34-3.40 (m, 1H),3.52-3.61 (m, 1H), 3.67-3.74 (m, 1H), 3.78-3.85 (m, 1H), 4.04 (s, 4H),4.16-4.24 (m, 1H), 4.55-4.64 (m, 1H), 7.01-7.06 (m, 1H), 7.18 (d, 1H),7.42 (s, 1H), 7.51-7.55 (m, 1H), 7.61-7.67 (m, 1H), 8.25-8.34 (m, 2H),13.42 (br. s, 1H).

Example 1072-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-yl)-1,7-naphthyridine

Intermediate-18 (0.10 g, 0.22 mmol) and 3,6-dihydro-2H-pyran-4-boronicacid pinacolester (95 mg, 0.43 mmol) were solubilised in dioxane (5 ml).Caesium carbonate (0.28 g, 0.87 mmol) and PdCl₂(dppf) in complex withdichloromethane (18 mg, 0.021 mmol) were added sequentially. Thereaction was heated for 4 hours in a sealed tube at 110° C.3,6-Dihydro-2H-pyran-4-boronic acid pinacolester (53 mg, 0.22 mmol) wasadded and the reaction was stirred for 48 hours at 110° C. The reactionwas then cooled to rt, diluted with water and extracted with ethylacetate. The organic phase was dried (MgSO₄), filtered and concentratedunder reduced pressure. The crude mixture was solubilised indichloromethane (6 ml) and 1M hydrochloric acid (1.2 ml) was added. Thereaction was stirred overnight and basified using a saturated solutionof sodium hydrogen carbonate. The reaction mixture was diluted withwater and extracted with dichloromethane. The organic phase was washedwith brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The crude material (42 mg) was solubilised in methanol (2 ml)and was hydrogenated in an autoclave (10.5 bar) at rt for 18 hours using10% Pd/C (20 mg). The reaction mixture was filtered through Celite® andconcentrated under reduced pressure. The crude material was purified byflash chromatography (hexane/ethyl acetate mixture) and the titlecompound was obtained in 10% yield (11 mg).

¹H-NMR (400 MHz, DMSO-d₆): d [ppm]=1.26 (d, 3H), 1.73-1.81 (m, 2H), 1.89(qd, 2H), 3.33-3.35 (m, 1H), 3.50-3.58 (m, 2H), 3.59-3.67 (m, 2H),3.70-3.75 (m, 1H), 3.79-3.84 (m, 1H), 3.96-4.09 (m, 3H), 4.19 (d, 1H),4.60-4.70 (m, 1H), 7.31 (s, 1H), 7.37 (s, 1H), 7.60 (s, 1H), 7.89 (d,1H), 8.37 (d, 1H), 13.36 (br. s., 1H).

Example 1084-(3,6-dihydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.30 g, 0.53 mmol),2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.25 g, 1.1 mmol), aq. potassium carbonate (0.85 ml, 2 M) andPdCl₂(PPh₃)₂ (40 mg, 0.056 mmol) were solubilised in dimethoxyethane (12ml). The reaction mixture was stirred for 10 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasdried by filtration and the filtrate was concentrated under reducedpressure. The crude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in dichloromethane andwashed with a saturated solution of sodium hydrogen carbonate. Theorganic phase was dried (silicon filter) and concentrated under reducedpressure. The title compound was obtained in 45% yield (100 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.27 (d, 3H), 2.56-2.62 (m, 2H), 2.93(t, 2H), 3.26-3.32 (m, 1H), 3.36-3.40 (m, 2H), 3.55 (td, 1H), 3.70 (dd,1H), 3.81 (d, 1H), 4.00-4.08 (m, 1H), 4.18 (d, 1H), 4.57-4.64 (m, 1H),6.00-6.04 (m, 1H), 7.30 (s, 1H), 7.38 (br. s., 1H), 7.58 (d, 1H), 7.62(br. s., 1H), 8.34 (d, 1H), 13.38 (br. s., 1H).

Example 1092-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylpiperidin-1-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.075 g, 0.14 mmol) was solubilised inN-methyl-2-pyrrolidone (2 ml) and 4-methylpiperidine (0.061, 51 mg, 0.50mmol) was added. The reaction mixture was stirred at 70° C. overnight.The mixture was cooled to rt, diluted with ethyl acetate and washed witha half saturated solution of sodium chloride. The organic phase wasdried (silicon filter) and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]=0.98 (d, 3H), 1.21 (d, 4H), 1.35-1.49 (m, 2H),1.49-1.63 (m, 1H), 1.75 (d, 2H), 2.69-2.82 (m, 2H), 3.19-3.28 (m, 1H),3.39-3.50 (m, 3H), 3.65 (dd, 1H), 3.77 (d, 1H), 4.03-4.10 (m, 1H), 4.52(dd, 1H), 6.69 (s, 1H), 7.30 (s, 1H), 7.51 (d, 1H), 7.56 (s, 1H), 8.26(d, 1H), 13.31 (br. s., 1H).

Example 1104-(1-tert-butyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.1 g, 0.19 mmol), 1-tert-butyl-1H-pyrazole-5-boronicacid pinacol ester (95 mg, 0.0.38 mmol), aq. potassium carbonate (0.81ml, 2 M) and PdCl₂(PPh₃)₂ (13 mg, 0.019 mmol) were solubilised indimethoxyethane (7 ml). The reaction mixture was stirred for 10 minutesat 130° C. under microwave irradiation. After cooling to rt, thereaction mixture was diluted with dichloromethane and dried byfiltration and the filtrate was concentrated under reduced pressure. Thecrude material was purified by preparative HPLC(acetonitrile/water/formic acid mixture). The combined fractions wereconcentrated under reduced pressure, solubilised in methanol (2 ml) andconcentrated hydrochloric acid (1 ml) was added. The mixture was stirredfor 2 hours at rt and then quenched with a saturated aqueous solution ofsodium hydrogen carbonate. The aqueous phase was extracted three timeswith dichloromethane. The organic phase was dried (silicon filter) andconcentrated under reduced pressure. The title compound was obtained in18% yield (15 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.21-1.31 (m, 3H), 1.38 (s, 9H),3.35-3.41 (m, 1H), 3.52-3.63 (m, 1H), 3.67-3.76 (m, 1H), 3.77-3.85 (m,1H), 4.00-4.10 (m, 1H), 4.17-4.27 (m, 1H), 4.56-4.65 (m, 1H), 6.34-6.40(m, 1H), 6.96 (t, 1H), 7.44 (s, 1H), 7.59-7.68 (m, 3H), 8.30-8.35 (m,1H), 13.44 (br. s, 1H).

Example 1112-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Intermediate-10 (0.5 g, 0.95 mmol),1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(415 mg, 1.9 mmol), aq. potassium carbonate (1.4 ml, 2 M) andPdCl₂(PPh₃)₂ (67 mg, 0.094 mmol) were solubilised in dimethoxyethane (60ml). The reaction mixture was stirred for 20 minutes at 130° C. undermicrowave irradiation. After cooling to rt, the reaction mixture wasfiltered through a silicon filter and concentrated under reducedpressure. The crude material was purified by flash column chromatography(hexane/ethyl acetate/ethanol mixture). The desired fractions wereconcentrated under reduced pressure and solubilised in conc. sulphuricacid (5 ml). The mixture was stirred for 3 h at rt. The mixture was thenpoured into ice and basified using solid sodium hydrogen carbonate. Thesuspension was filtered and the solid was stirred with ethanol at 40°C., filtered and dried under reduced pressure. The title compound wasobtained in 78% yield (0.28 g).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.30 (d, 3H), 3.30-3.40 (m, 1H),3.51-3.62 (m, 1H), 3.68-3.77 (m, 4H), 3.79-3.86 (m, 1H), 4.01-4.09 (m,1H), 4.18-4.28 (m, 1H), 4.60-4.69 (m, 1H), 6.59 (d, 1H), 7.27 (d, 1H),7.42 (s, 1H), 7.60 (s, 1H), 7.63-7.69 (m, 2H), 8.35 (d, 1H), 13.42 (br.s, 1H).

Example 1122-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1,2-oxazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1,2-oxazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-w1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 79 mg (0.38 mmol)3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole, 15mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1,2-oxazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 160 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1,2-oxazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 6.7 ml of methanol and 0.35 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with a saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 4 mg (0.01mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 2.40 (3H), 3.37 (1H),3.51-3.64 (1H), 3.73 (1H), 3.84 (1H), 4.00-4.11 (1H), 4.23 (1H),4.58-4.72 (1H), 7.22 (1H), 7.36-7.44 (1H), 7.59-7.67 (1H), 7.79 (1H),7.92 (1H), 8.43 (1H), 13.36-13.48 (1H).

Example 1134-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 90 mg (0.38 mmol)1-ethyl-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 127 mg of crude4-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.5 ml of methanol and 0.26 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with a saturated aqueous sodium bicarbonate solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and concentrated to dryness. The residuewas purified by preparative HPLC (Autopurifier: basic conditions) togive 18 mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.20 (3H), 1.29 (3H), 2.28 (3H),3.51-3.63 (1H), 3.72 (1H), 3.82 (1H), 3.89 (2H), 4.05 (1H), 4.22 (1H),4.63 (1H), 6.33 (1H), 7.24 (1H), 7.43 (1H), 7.54 (1H), 7.64 (1H), 8.35(1H), 13.44 (1H).

Example 1144-(1,4-dimethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)1(1,4-dimethyl-1H-pyrazol-5-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 102 mg of crude4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 4.2 ml of methanol and 0.22 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 1.88 (3H), 3.49-3.69 (4H),3.69-3.76 (1H), 3.82 (1H), 4.06 (1H), 4.25 (1H), 4.64 (1H), 7.05 (1H),7.44 (1H), 7.50 (1H), 7.58 (1H), 7.65 (1H), 8.35 (1H), 13.44 (1H).

Example 1154-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 26 mg (0.14 mmol)[2-methyl-6-(methylsulfanyl)pyridin-3-yl]boronic acid, 11 mg (0.014mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) ofpotassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave reactor. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 119 mg of crude4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.5 ml of methanol and 0.23 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 15 mg (0.04mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 2.24 (3H), 2.55-2.63 (3H),3.49-3.64 (1H), 3.72 (1H), 3.82 (1H), 3.98-4.13 (1H), 4.22 (1H), 4.61(1H), 7.05 (1H), 7.32 (1H), 7.37-7.53 (2H), 7.53-7.70 (2H), 8.30 (1H),13.42 (1H).

Example 1164-[2-methyl-6-(S-methylsulfonimidoyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 250 mg (0.47 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 87 mg (0.47 mmol)[2-methyl-6-(methylsulfanyl)pyridin-3-yl]boronic acid, 38 mg (0.047mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 164 mg (1.19 mmol)of potassium carbonate in 10.0 ml of MeCN and 3.3 ml water was degasedwith argon. Under argon, the reaction mixture was stirred at 130° C. for10 minutes in a microwave reactor. After cooling the reaction mixturewas diluted with saturated aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated. The residue waspurified by column chromatography (gradient from 100% Hex to 100% EtOAc)to give 170 mg (0.33 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.15-1.35 (3H), 1.46 (2H), 1.52-1.69(1H), 1.88-2.07 (2H), 2.25 (3H), 2.30-2.45 (1H), 2.56-2.64 (3H),3.14-3.29 (2H), 3.39-3.55 (1H), 3.58-3.68 (1H), 3.68-3.82 (2H), 3.97(1H), 4.18 (1H), 4.52 (1H), 6.08-6.22 (1H), 6.93-7.06 (1H), 7.10 (1H),7.32 (1H), 7.37-7.48 (1H), 7.56-7.68 (2H), 8.33 (1H).

Step b2,2,2-trifluoro-N-[methyl(6-methyl-5-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-yl)-λ⁴-sulfanylidene]acetamide

Under an atmosphere of argon, a solution of 43 mg (0.38 mmol)2,2,2-trifluoroacetamide in 0.20 ml THF was added dropwise to a solutionof 24 mg (0.25 mmol) sodium tert.-butoxide in 0.25 ml THF, so that thetemperature of the mixture remained below 10° C. Subsequently, a freshlyprepared solution of 47 mg (0.16 mmol) 1,3-dibromo-5,5-dimethylhydantoinin 0.25 ml THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. Then the mixture wasstirred for 10 minutes at 10° C. Finally, a solution of 130 mg (0.25mmol)4-[2-methyl-6-(methylsulfanyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 0.8 ml THF was added dropwise to the stirred mixture, so that thetemperature of the mixture remained below 10° C. The mixture was stirredfor 3 hours at 10° C. and then at room temperature overnight. The batchwas diluted with 1.0 ml toluene under cooling and an aqueous solution of32 mg (0.25 mmol) sodium sulfite in 0.9 ml water was added so that thetemperature of the mixture remained below 15° C. The batch was extractedthree times with ethyl acetate. The combined organic phases were washedwith an aqueous solution of sodium chloride, filtered using a Whatmanfilter and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate) to give 28 mg of thedesired product containing slight impurities.

Step c4-[2-methyl-6-(S-methylsulfonimidoyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

28 mg (0.045 mmol)2,2,2-trifluoro-N-[methyl(6-methyl-5-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-yl)-λ4-sulfanylidene]acetamidewas dissolved in 0.87 ml methanol. To this solution 0.31 ml water wasadded. The pH was adjusted to 10.5 by addition of an aqueous solution ofpotassium hydroxide (25%). 23 mg (0.038 mmol) Oxone® was added and themixture was stirred at room temperature for 5 hours. Additional amount23 mg (0.038 mmol) Oxone® was added. The pH was adjusted to 10.5 byaddition of an aqueous solution of potassium hydroxide (25%). The batchwas stirred at room temperature for 3 hours. The batch was filtered andthe filtrate was adjusted to pH 6-7 by the addition of 1N aqueoushydrogen chloride solution. The mixture was diluted with aqueous sodiumchloride solution and extracted with DCM (2×). The combined organicphases were washed with an aqueous solution of sodium sulfite (10%),filtered using a Whatman filter, and concentrated to give 10 mg crudeproduct that was used without further purification.

Step d4-[2-methyl-6-(S-methylsulfonimidoyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 10 mg of crude4-[2-methyl-6-(S-methylsulfonimidoyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step c in 1.0 ml of methanol and 0.02 ml of 2N hydrochloric acidwas stirred for 2 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: acidic conditions) to give 2 mg (0.004mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.23-1.40 (3H), 2.22-2.41 (3H), 3.25(3H), 3.38 (1H), 3.46-3.65 (1H), 3.72 (1H), 3.82 (1H), 4.05 (1H),4.13-4.32 (1H), 4.53 (1H), 4.62 (1H), 6.91-7.11 (1H), 7.46 (1H), 7.58(1H), 7.66 (1H), 7.99-8.17 (2H), 8.31 (1H).

Example 1172-[(3R)-3-methylmorpholin-4-yl]-4-(1-propyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(1-propyl-1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 34 mg (0.14 mmol)1-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 11mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) of potassiumcarbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(1-propyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 110 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(1-propyl-1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.4 ml of methanol and 0.23 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.03mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.64 (3H), 1.29 (3H), 1.63 (2H), 3.34(1H), 3.59 (1H), 3.73 (1H), 3.82 (1H), 3.89-4.02 (2H), 4.02-4.12 (1H),4.23 (1H), 4.63 (1H), 6.55 (1H), 7.21 (1H), 7.44 (1H), 7.57 (1H),7.60-7.74 (2H), 8.35 (1H), 13.43 (1H).

Example 1184-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 57 mg (0.38 mmol)6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-ylboronic acid, 15 mg (0.019mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) ofpotassium carbonate in 2.0 ml of MeCN and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave reactor. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 166 mg of crude4-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.2 ml of methanol and 0.34 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.19-1.42 (3H), 2.54-2.71 (2H),2.81-3.00 (2H), 3.58 (1H), 3.73 (1H), 3.84 (1H), 3.97-4.15 (3H), 4.21(1H), 4.63 (1H), 7.29-7.51 (3H), 7.64 (1H), 7.78 (1H), 8.37 (1H), 13.42(1H).

Example 1194-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 30 mg (0.14 mmol)[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid, 11 mg (0.014mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) ofpotassium carbonate in 3.0 ml of MeCN and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave reactor. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 118 mg of crude4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.2 ml of methanol and 0.22 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.11-1.38 (6H), 3.36 (1H), 3.58 (1H),3.72 (1H), 3.83 (1H), 4.07 (3H), 4.24 (1H), 4.64 (1H), 7.10 (1H), 7.17(1H), 7.36-7.48 (1H), 7.66 (1H), 7.72 (1H), 8.36 (1H), 13.40 (1H).

Example 120 methyl5-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrrole-2-carboxylateStep a 1-tert-butyl 2-methyl5-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-1H-pyrrole-1,2-dicarboxylate

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 38 mg (0.14 mmol)[1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-1H-pyrrol-2-yl]boronicacid, 11 mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) of potassiumcarbonate in 3.0 ml of MeCN and 1.0 ml water was degased with argon.Under argon, the reaction mixture was stirred at 130° C. for 10 minutesin a microwave reactor. After cooling the reaction mixture was dilutedwith saturated aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b methyl5-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrrole-2-carboxylate

A solution of 115 mg of crude 1-tert-butyl 2-methyl5-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-1H-pyrrole-1,2-dicarboxylatefrom step a in 5.5 ml of methanol and 0.23 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous chloride solution and extracted withethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (3H), 3.36-3.44 (1H), 3.52-3.65(1H), 3.72 (1H), 3.78-3.93 (4H), 3.99-4.16 (1H), 4.24 (1H), 4.66 (1H),6.72 (1H), 7.03 (1H), 7.39 (1H), 7.49-7.59 (1H), 7.59-7.70 (1H), 7.84(1H), 8.38 (1H), 12.60 (1H), 13.40 (1H).

Example 1212-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2-thiazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-(1,2-thiazol-5-yl)-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 80 mg (0.38 mmol)5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole, 15 mg(0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of ceasiumcarbonate in 1.3 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2-thiazol-5-yl)-1,7-naphthyridine

A solution of 155 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-(1,2-thiazol-5-yl)-1,7-naphthyridinefrom step a in 1.5 ml of methanol and 0.39 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.40 (1H), 3.57 (1H), 3.72(1H), 3.83 (1H), 4.05 (1H), 4.17-4.34 (1H), 4.59-4.83 (1H), 7.41 (1H),7.57-7.75 (3H), 7.89 (1H), 8.40 (1H), 8.80 (1H), 13.39 (1H).

Example 122N,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}anilineStep aN,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}aniline

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 63 mg (0.38 mmol)[2-(dimethylamino)phenyl]boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of ceasiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step bN,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}aniline

A solution of 180 mg of crudeN,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}anilinefrom step a in 1.7 ml of methanol and 0.42 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 40 mg (0.10mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.28 (3H), 2.45 (6H), 3.60 (1H),3.70-3.78 (1H), 3.78-3.86 (1H), 3.97-4.12 (1H), 4.21 (1H), 4.59 (1H),7.03-7.19 (2H), 7.19-7.29 (2H), 7.36-7.54 (3H), 7.64 (1H), 8.25 (1H),13.40 (1H).

Example 1234-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 60 mg (0.38 mmol) (2,4-difluorophenyl)boronicacid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofceasium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 90 minutes. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 126 mg of crude4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.7 ml of methanol and 0.26 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 3.38 (1H), 3.57 (1H),3.68-3.75 (1H), 3.82 (1H), 4.05 (1H), 4.22 (1H), 4.64 (1H), 7.17 (1H),7.31-7.38 (1H), 7.42 (1H), 7.49-7.58 (2H), 7.60-7.70 (2H), 8.32 (1H),13.18 (1H).

Example 1244-(1-isopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-isopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 58 mg (0.38 mmol)(1-isopropyl-1H-pyrazol-5-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of ceasiumcarbonate in 2.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 60 minutes. After coolingthe reaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-(1-isopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 126 mg of crude4-(1-isopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 4.0 ml of methanol and 0.20 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 14 mg(0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (9H), 3.59 (1H), 3.72 (1H), 3.82(1H), 4.06 (1H), 4.13-4.31 (2H), 4.52-4.74 (1H), 6.51 (1H), 7.14 (1H),7.43 (1H), 7.54 (1H), 7.66 (1H), 7.71 (1H), 8.35 (1H), 13.43 (1H).

Example 125 ethylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinateStep a ethylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinate

A mixture of 250 mg (0.47 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.47 mmol) ethyl methylphosphinate, 2mg (0.009 mmol) palladium(II) acetate, 6 mg (0.01 mmol) of1,1′-bis(diphenylphosphino)ferrocene and 0.11 ml (0.62 mmol) ofethyldiisopropylamine in 2.1 ml of DMF and 0.24 ml 1,2-dimethoxyethanewas degased with argon. Under argon, the reaction mixture was stirred atroom temperature for 10 minutes and then at 110° C. overnight. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution. The aqueous phase was saturated with solidsodium chloride and extracted with a mixture of THF and ethyl acetet(1:1). The combined organic phases were filtered using a Whatman filterand then concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b ethylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinate

A solution of 310 mg of crude ethylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinatefrom step a in 2.9 ml of methanol and 0.75 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 15 mg of anapparent salt of the desired product. The material was taken up in 13 mlof ethyl acetate and 2 ml of saturated aqueous sodium chloride solutionand the mixture was stirred for 15 minutes. The mixture was filteredusing a Whatman filter and concentrated to give 8 mg (0.02 mmol) of thedesired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.18-1.28 (3H), 1.28-1.37 (3H),1.81-1.97 (3H), 3.58 (1H), 3.72 (1H), 3.85 (1H), 3.88-3.98 (1H),4.00-4.12 (2H), 4.12-4.21 (1H), 4.60 (1H), 7.37 (1H), 7.65 (1H), 7.80(1H), 8.11 (1H), 8.33-8.51 (1H), 13.45 (1H).

Example 1264-{[diethyl(oxido)-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-{[diethyl(oxido)-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 8 mg (0.014 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75mg (0.142 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 22 mg (0.19 mmol)(S-ethylsulfonimidoyl)ethane and 69 mg (0.21 mmol) caesium carbonate in0.67 ml toluene. The mixture was stirred at 110° C. for 3 hours. Aftercooling, the reaction mixture was diluted with ethyl acetate and washedwith an aqueous solution of sodium chloride. The organic phase wasfiltered using a Whatman filter and concentrated to give the crudeproduct that was used without further purification.

Step b4-{[diethyl(oxido)-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.14 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 71 mg crude4-{[diethyl(oxido)-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 3.2 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 25 mg (0.06 mmol) of thedesired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (3H), 1.29-1.40 (6H), 3.20-3.31(1H), 3.48-3.67 (5H), 3.71 (1H), 3.83 (1H), 3.94-4.14 (2H), 4.39 (1H),6.84 (s, 1H), 7.34 (1H), 7.60 (1H), 7.88 (1H), 8.29 (1H), 13.35 (1H).

Example 127 isobutylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinateStep a isobutylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinate

A mixture of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 26 mg (0.19 mmol) methylphosphonic acidisobutylester, 1 mg (0.004 mmol) palladium(II) acetate, 2 mg (0.004mmol) of 1,1′-bis(diphenylphosphino)ferrocene and 0.01 ml (0.25 mmol) ofethyldiisopropylamine in 0.9 ml of DMF and 0.1 ml 1,2-dimethoxyethanewas degased with argon. Under argon, the reaction mixture was stirred atroom temperature for 10 minutes and then at 110° C. overnight. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution. The aqueous phase was saturated with solidsodium chloride and extracted with a mixture of THF and ethyl acetet(1:1). The combined organic phases were filtered using a Whatman filterand then concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b isobutylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinate

A solution of 135 mg of crude isobutylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinatefrom step a in 1.2 ml of methanol and 0.3 ml of 2N hydrochloric acid wasstirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 26 mg (0.06mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.88 (6H), 1.31 (3H), 1.90 (3H),3.30-3.45 (1H), 3.52-3.64 (2H), 3.72 (1H), 3.76-3.91 (2H), 4.07 (1H),4.11-4.27 (2H), 4.47-4.71 (1H), 7.37 (1H), 7.64 (1H), 7.79 (1H), 8.10(1H), 8.44 (1H), 13.41 (1H).

Example 1282-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}propan-2-olStep a methyl2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylate

In an autoclave, a mixture of 2527 mg (4.79 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 203 mg (0.48 mmol)1,3-bis(diphenylphosphino)propane, 108 mg (0.48 mmol) palladium(II)acetate and 1.3 ml triethylamine (9.6 mmol) in 34 ml of DMF and 18 ml ofmethanol was purged with carbon monoxide at room temperature. Theautoclave was pressured with carbonmonoxide to 16.5 bar and the mixturewas stirred at room temperature for 30 minutes. The autoclave wasdepressurized and then pressured with carbon monoxide to 20.9 bar. Themixture was stirred at 80° C. for 20 hours. The autoclave wasdepressurized and after cooling, the mixture was diluted with water andextracted with ethyl acetate (2×). The combined organic phases weredried (Na₂SO₄), filtered and concentrated. The residue was purified bycolumn chromatography (gradient from 100% Hex to 100% EtOAc) to give1537 mg (3.51 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.22 (3H), 1.35-1.52 (2H), 1.52-1.72(1H), 1.82-2.05 (2H), 2.28-2.45 (1H), 3.14-3.31 (2H), 3.43-3.57 (1H),3.57-3.85 (3H), 3.91-4.05 (4H), 4.12 (1H), 4.40-4.61 (1H), 5.90-6.18(1H), 6.89 (1H), 7.59-7.68 (1H), 7.86 (1H), 8.19 (1H), 8.47 (1H).

Step b2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}propan-2-ol

0.23 ml (0.69 mmol) of a 3.0 M solution of methylmagnesium bromide indiethylether was added dropwise to a stirred solution of 100 mg (0.23mmol) methyl2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylatein 3.8 ml of THF at 0° C. The mixture was stirred at 0° C. for 30minutes and then the icebath was removed and the mixture was stirred atroom temperature for 150 minutes. The mixture was diluted with asaturated aqueous solution of ammonium chloride and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step c2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}propan-2-ol

A solution of 91 mg of crude2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}propan-2-olfrom step b in 1.8 ml of methanol and 0.21 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 14 mg (0.04mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.28 (3H), 1.69 (6H), 3.57 (1H), 3.72(1H), 3.84 (1H), 4.06 (1H), 4.09-4.18 (1H), 4.58 (1H), 5.59 (1H), 7.35(1H), 7.42 (1H), 7.61 (1H), 8.26-8.38 (2H), 13.35 (1H).

Example 1293-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pentan-3-olStep a3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pentan-3-ol

0.46 ml (1.37 mmol) of a 3.0 M solution of ethylmagnesium bromide indiethylether was added dropwise to a stirred solution of 200 mg (0.46mmol) methyl2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylatein 7.7 ml of THF at 0° C. The mixture was stirred at 0° C. for 30minutes and then the icebath was removed and the mixture was stirred atroom temperature for 150 minutes. The mixture was diluted with asaturated aqueous solution of ammonium chloride and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pentan-3-ol

A solution of 211 mg of crude3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pentan-3-olfrom step a in 5.0 ml of methanol and 0.45 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: acidic conditions) to give 6 mg (0.02mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.66 (6H), 1.26 (3H), 1.84-2.07 (2H),2.17 (2H), 3.59 (1H), 3.75 (1H), 3.84 (1H), 3.99-4.15 (2H), 4.51 (1H),5.17 (1H), 7.35 (1H), 7.53 (1H), 7.61 (1H), 8.11 (1H), 8.31 (1H), 13.34(1H).

Example 1304-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 45 mg (0.28 mmol)(5-chloropyridin-3-yl)boronic acid, 11 mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 185 mg (0.57 mmol) ofcaesium carbonate in 1.0 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 90 minutes. Aftercooling the reaction mixture was diluted with saturated aqueous ammoniumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 120 mg of crude4-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.0 ml of methanol and 0.24 ml of 2N hydrochloric acidwas stirred for 2 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 8 mg (0.02mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.36-3.41 (1H), 3.57 (1H),3.72 (1H), 3.84 (1H), 4.06 (1H), 4.25 (1H), 4.55-4.77 (1H), 7.38 (1H),7.43 (1H), 7.59 (1H), 7.66 (1H), 8.26 (1H), 8.35 (1H), 8.75 (1H), 8.83(1H), 13.34 (1H).

Example 1315-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}anilineStep a5-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}aniline

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 90 mg (0.38 mmol)5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 15 mg(0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b5-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}aniline

A solution of 147 mg of crude5-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}anilinefrom step a in 5.8 ml of methanol and 0.30 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 14 mg(0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.48-3.65 (1H), 3.66-3.77(1H), 3.82 (1H), 4.05 (1H), 4.15-4.30 (1H), 4.50-4.73 (1H), 5.20 (2H),6.37-6.54 (1H), 6.58 (1H), 7.04 (1H), 7.14 (1H), 7.35 (1H), 7.44 (1H),7.64 (1H), 8.28 (1H), 13.41 (1H).

Example 1324-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 57 mg (0.19 mmol)2-[2-fluoro-3-(methylsulfonyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 2.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 90 minutes. After coolingthe reaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 105 mg of crude4-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.19 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 14 mg(0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (3H), 3.36-3.44 (4H), 3.58 (1H),3.72 (1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.18 (1H), 7.44(1H), 7.52-7.82 (3H), 7.90-8.02 (1H), 8.02-8.16 (1H), 8.34 (1H), 13.43(1H).

Example 1332-[(3R)-3-methylmorpholin-4-yl]-4-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 94 mg (0.38 mmol)1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 119 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(oxetan-3-yl)-1H-pyrazol-5-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.24 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 11 mg(0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.19-1.39 (3H), 3.57 (1H), 3.72 (1H),3.83 (1H), 4.06 (1H), 4.21 (1H), 4.62 (1H), 4.73 (2H), 5.00 (2H),5.25-5.44 (1H), 6.65 (1H), 7.09 (1H), 7.43 (1H), 7.48 (1H), 7.58-7.71(1H), 7.88 (1H), 8.26-8.40 (1H), 13.45 (1H).

Example 1344-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 79 mg (0.38 mmol)[2-fluoro-4-(pyrrolidin-1-yl)phenyl]boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 180 mg of crude4-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.5 ml of methanol and 0.38 ml of 2N hydrochloric acidwas stirred for 1 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 44 mg(0.10 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 1.96-2.07 (4H), 3.27-3.33(4H), 3.58 (1H), 3.72 (1H), 3.82 (1H), 4.05 (1H), 4.14-4.25 (1H),4.56-4.70 (1H), 6.47-6.58 (2H), 7.24-7.48 (4H), 7.64 (1H), 8.31 (1H),13.41 (1H).

Example 1354-[3-(methoxymethyl)-5-methyl-1,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[3-(methoxymethyl)-5-methyl-1,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 24 mg (0.14 mmol)[3-(methoxymethyl)-5-methyl-1,2-oxazol-4-yl]boronic acid, 11 mg (0.014mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) ofpotassium carbonate in 3.0 ml of acetonitrile and 1.0 ml water wasdegased with argon. Under argon, the reaction mixture was stirred at130° C. for 10 minutes in a microwave oven. After cooling the reactionmixture was diluted with saturated aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-[3-(methoxymethyl)-5-methyl-1,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 111 mg of crude4-[3-(methoxymethyl)-5-methyl-1,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.22 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 11 mg (0.02mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25-1.36 (3H), 2.34 (3H), 3.09 (3H),3.37 (1H), 3.59 (1H), 3.73 (1H), 3.83 (1H), 4.07 (1H), 4.20 (1H), 4.37(1H), 4.50 (1H), 4.54-4.64 (1H), 7.29 (1H), 7.41 (1H), 7.55 (1H), 7.65(1H), 8.34 (1H), 13.14 (1H).

Example 1362-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carbohydrazide

0.06 ml (1.14 mmol) hydrazine hydrate was added to a solution of 50 mg(0.11 mmol) of methyl2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylatein 2 ml of ethanol and the mixture was stirred at 100° C. for 5 hours.The mixture was concentrated to give the crude product that was usedwithout further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

0.03 ml (0.34 mmol) trifluoroacetic acid was added to a solution ofcrude2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carbohydrazidefrom step a in 1.5 ml of trimethyl orthoacetate. The mixture was stirredat 95° C. for 60 minutes. After cooling the reaction mixture wasconcentrated to give the crude product that was used without furtherpurification in the next step.

Step c2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 47 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step bin 3.0 ml of methanol and 0.10 ml of 2N hydrochloric acid wasstirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 5 mg (0.01mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 2.63-2.82 (3H), 3.37-3.46(1H), 3.59 (1H), 3.74 (1H), 3.85 (1H), 4.08 (1H), 4.21 (1H), 4.65 (1H),7.40 (1H), 7.66 (1H), 7.96 (1H), 8.49 (1H), 8.62 (1H), 13.45 (1H).

Example 137N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}tetrahydro-1H-1λ⁴-thiophen-1-imine1-oxide Step aN-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}tetrahydro-1H-1λ⁴-thiophen-1-imine1-oxide

Under argon, 8 mg (0.014 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75mg (0.142 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 22 mg (0.19 mmol)tetrahydro-1H-1λ⁴-thiophen-1-imine 1-oxide and 69 mg (0.21 mmol) caesiumcarbonate in 0.67 ml toluene. The mixture was stirred at 110° C. for 3hours. After cooling, the reaction mixture was diluted with ethylacetate and washed with an aqueous solution of sodium chloride. Theorganic phase was filtered using a Whatman filter and concentrated togive the crude product that was used without further purification.

Step bN-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}tetrahydro-1H-1λ⁴-thiophen-1-imine1-oxide

0.15 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 72 mg crudeN-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}tetrahydro-1H-1λ⁴-thiophen-1-imine1-oxide in 3.3 ml methanol and the reaction mixture was stirred at roomtemperature for 1 hour. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 26 mg (0.06 mmol) of thedesired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.26 (3H), 2.07-2.24 (2H), 2.24-2.37(2H), 3.18-3.30 (1H), 3.44-3.69 (5H), 3.72 (1H), 3.83 (1H), 3.95-4.13(2H), 4.44 (1H), 6.67 (1H), 7.35 (1H), 7.60 (1H), 7.89 (1H), 8.29 (1H),13.36 (1H).

Example 1384-{[(4-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,mixture of 2 diastereoisomers Step a4-{[(4-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 8 mg (0.014 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75mg (0.142 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 32 mg (0.19 mmol)1-fluoro-4-(S-methylsulfonimidoyl)benzene and 69 mg (0.21 mmol) caesiumcarbonate in 0.67 ml toluene. The mixture was stirred at 110° C. for 3hours. After cooling, the reaction mixture was diluted with ethylacetate and washed with an aqueous solution of sodium chloride. Theorganic phase was filtered using a Whatman filter and concentrated togive the crude product that was used without further purification.

Step b4-{[(4-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,mixture of 2 diastereoisomers

0.23 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 125 mg crude4-{[(4-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 5.1 ml methanol and the reaction mixture was stirred at roomtemperature for 90 minutes. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 24 mg (0.05 mmol) of thedesired product as a mixture of 2 stereoisomers.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.82 (3H), 1.16 (3H), 3.00-3.17 (2H),3.41-3.55 (2H), 3.55-3.67 (2H), 3.67-3.78 (8H), 3.78-3.92 (2H), 3.98(3H), 4.14 (1H), 6.44 (1H), 6.56 (1H), 7.28 (2H), 7.49 (4H), 7.56 (2H),7.92-8.17 (6H), 8.33 (2H), 13.29 (2H).

Example 1394-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,mixture of 2 diastereoisomers Step a4-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

Under argon, 8 mg (0.014 mmol)4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 7 mg (0.007 mmol)tris(dibenzylideneacetone)dipalladium(0) were added to a mixture of 75mg (0.142 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 32 mg (0.19 mmol)1-fluoro-2-(S-methylsulfonimidoyl)benzene and 69 mg (0.21 mmol) caesiumcarbonate in 0.67 ml toluene. The mixture was stirred at 110° C. for 3hours. After cooling, the reaction mixture was diluted with ethylacetate and washed with an aqueous solution of sodium chloride. Theorganic phase was filtered using a Whatman filter and concentrated togive the crude product that was used without further purification.

Step b4-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,mixture of 2 diastereoisomers

0.20 ml (0.29 mmol) 2N aqueous solution of hydrogen chloride was addedto a solution of 110 mg crude4-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinein 4.5 ml methanol and the reaction mixture was stirred at roomtemperature for 90 minutes. The mixture was basified by addition of anaqueous sodium bicarbonate solution and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand concentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 28 mg (0.06 mmol) of thedesired product as a mixture of 2 stereoisomers.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.82 (3H), 1.15 (3H), 2.99-3.17 (2H),3.46 (2H), 3.57 (1H), 3.60-3.67 (1H), 3.71 (2H), 3.74-3.92 (8H),3.92-4.06 (3H), 4.12 (1H), 6.47 (1H), 6.52 (1H), 7.27 (2H), 7.38-7.54(4H), 7.56 (2H), 7.73-7.84 (2H), 7.91-7.96 (2H), 8.11 (1H), 8.11 (1H),8.27-8.34 (2H), 13.28 (2H).

Examples 140 and 1414-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,diastereoisomer 14-{[(2-fluorophenyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine,diasteroisomer 2

The mixture of 2 stereoisomers from example 139 was separated into thesingle stereoisomers using preparative chiral HPLC:

System: Labomatic Pump HD-5000, Labomatic SP-3000, Labocord 5000,Labomatic Labcol Vario 4000, Gilson GX-241 Column: Chiralpak IA 5 μm 250× 30 mm Solvent: EtOH/Methanol/diethylamine 50:50:0.1 (v/v/v) Flow: 35mL/min Temperature: RT Solution: 25 mg/3 mL DCM/MeOH Injection: 5 × 0.6mL Detection: UV 254 nm Retention time in min purity in % yield Example140 7.4-7.9 93 6 mg Stereoisomer 1 (0.01 mmol) Example 141 8.6-9.2 93 6mg Stereoisomer 2 (0.01 mmol)

Example 1424-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 35 mg (0.32 mmol) dimethylphosphinoxide, 33mg (0.028 mmol tetrakis(triphenylphosphine)palladium(0) and 0.06 ml(0.43 mmol) of triethylamine in 0.9 ml of acetonitrile was degased withargon. Under argon, the reaction mixture was stirred at 90° C. for 3hours. After cooling the reaction mixture was diluted with ethyl acetateand washed with aqueous chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 210 mg of crude4-(dimethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.1 ml of methanol and 0.53 ml of 2N hydrochloric acidwas stirred for 10 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 13 mg (0.04mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 1.94 (3H), 1.90 (3H),3.36-3.43 (1H), 3.57 (1H), 3.72 (1H), 3.85 (1H), 4.07 (1H), 4.18 (1H),4.55-4.71 (1H), 7.37 (1H), 7.54-7.74 (2H), 8.32-8.51 (2H), 13.40 (1H).

Example 1434-(diethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(diethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 32 mg (0.28 mmol) diethylphosphane oxide, 1.3mg (0.006 mmol) palladium(II) acetate, 3.5 mg (0.006 mmol) of1,1′-bis(diphenylphosphino)ferrocene and 0.06 ml (0.37 mmol) ofethyldiisopropylamine in 1.2 ml of DMF and 0.14 ml 1,2-dimethoxyethanewas degased with argon. Under argon, the reaction mixture was stirred atroom temperature for 10 minutes and then at 110° C. overnight. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution. The aqueous phase was saturated with solidsodium chloride and extracted with a mixture of THF and ethyl acetet(1:1). The combined organic phases were filtered using a Whatman filterand then concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b4-(diethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 190 mg of crude4-(diethylphosphoryl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.8 ml of methanol and 0.45 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 25 mg (0.06mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.89-1.12 (6H), 1.18-1.35 (3H),2.09-2.31 (4H), 3.59 (1H), 3.74 (1H), 3.84 (1H), 4.07 (1H), 4.18 (1H),4.62 (1H), 7.37 (1H), 7.54-7.81 (2H), 8.39 (1H), 8.50 (1H), 13.40 (1H).

Example 144 ethylisobutyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinateStep a ethylisobutyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinate

A mixture of 250 mg (0.47 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 71 mg (0.47 mmol) ethyl(2-methylpropyl)phosphinate, 2.1 mg (0.009 mmol) palladium(II) acetate,5.8 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocene and 0.11 ml(0.62 mmol) of ethyldiisopropylamine in 2.1 ml of DMF and 0.24 ml1,2-dimethoxyethane was degased with argon. Under argon, the reactionmixture was stirred at room temperature for 10 minutes and then at 110°C. overnight. After cooling the reaction mixture was diluted with ethylacetate and washed with saturated aqueous sodium bicarbonate solutionand saturated aqueous sodium chloride solution. The aqueous phase wassaturated with solid sodium chloride and extracted with a mixture of THFand ethyl acetet (1:1). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b ethylisobutyl{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phosphinate

A solution of 456 mg of crude ethylisobutyl{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phosphinatefrom step a in 3.9 ml of methanol and 1.0 ml of 2N hydrochloric acid wasstirred for 60 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 29 mg (0.07mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.79-0.96 (3H), 1.03 (3H), 1.13-1.42(6H), 1.90-2.19 (4H), 3.59 (1H), 3.73 (1H), 3.79-3.93 (2H), 3.97-4.27(3H), 4.42-4.72 (1H), 7.38 (1H), 7.64 (1H), 7.81 (1H), 8.10 (1H), 8.45(1H), 13.42 (1H).

Example 1452-[(3R)-3-methylmorpholin-4-yl]-4-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 50 mg (0.095 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 28 mg (0.32 mmol) morpholine in 0.14 ml ofMeCN was stirred at 70° C. for 150 minutes under argon. After coolingthe reaction mixture was diluted with ethyl acetate and THF and washedwith saturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 45 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinelfrom step a in 0.45 ml of methanol and 0.11 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 16mg (0.04 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (3H), 3.07-3.23 (4H), 3.54 (1H),3.69 (1H), 3.77-3.91 (5H), 3.98-4.07 (1H), 4.11 (1H), 4.57 (1H), 6.77(1H), 7.33 (1H), 7.59 (1H), 7.63 (1H), 8.29 (1H), 13.33 (1H).

Example 1464-(1-isobutyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-isobutyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 36 mg (0.14 mmol)1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,11 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 49 mg (0.36 mmol) of potassiumcarbonate in 3.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-(1-isobutyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 105 mg of crude4-(1-isobutyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.21 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:acidic conditions) to give 8 mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.64 (6H), 1.16-1.36 (3H), 1.82-2.04(1H), 3.50-3.67 (1H), 3.69-3.96 (4H), 3.98-4.14 (1H), 4.23 (1H), 4.62(1H), 6.56 (1H), 7.23 (1H), 7.44 (1H), 7.57 (1H), 7.65 (1H), 7.71 (1H),8.36 (1H), 13.43 (1H).

Example 1474-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 86 mg (0.28 mmol)3-fluoro-2-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 12 mg (0.014 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 185 mg (0.57 mmol) of caesiumcarbonate in 1.0 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b4-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 118 mg of crude4-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.0 ml of methanol and 0.25 ml of 2N hydrochloric acidwas stirred for 1 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 1 mg(0.002 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.27-1.33 (3H), 3.45-3.63 (5H), 3.71(1H), 3.83 (1H), 4.05 (1H), 4.23 (1H), 4.65 (1H), 7.33-7.54 (2H), 7.64(2H), 8.34 (1H), 8.43 (1H), 8.80 (1H), 13.42 (1H).

Example 1484-[(3R)-3-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(3R)-3-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 100 mg (0.99 mmol) (3R)-3-methylmorpholinein 0.43 ml of MeCN was stirred at 70° C. overnight under argon. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-[(3R)-3-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 190 mg of crude4-[(3R)-3-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.9 ml of methanol and 0.47 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 18mg (0.05 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.93 (3H), 2.82 (1H), 3.38-3.47 (1H),3.54 (1H), 3.65-3.86 (10H), 3.91 (1H), 3.98 (1H), 6.96 (1H), 7.36 (1H),7.61 (1H), 7.71 (1H), 8.33 (1H), 13.35 (1H).

Example 1492-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 48 mg (0.38 mmol)1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 111 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.0 ml of methanol and 0.24 ml of 2N hydrochloric acidwas stirred for 60 minutes at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:acidic conditions) to give 12 mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.30 (3H), 2.07 (3H), 3.59 (1H), 3.73(1H), 3.83 (1H), 4.06 (1H), 4.20 (1H), 4.62 (1H), 7.25-7.52 (2H), 7.64(2H), 7.76 (1H), 8.34 (1H), 13.11 (1H), 13.41 (1H).

Example 1504-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 83 mg (0.38 mmol)[2-fluoro-5-(methylsulfonyl)phenyl]boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 83 mg of crude4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.15 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:acidic conditions) to give 29 mg (0.06 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.32 (3H), 3.37 (1H), 3.35 (3H), 3.58(1H), 3.72 (1H), 4.05 (1H), 4.21 (1H), 4.65 (1H), 7.17 (1H), 7.45 (1H),7.65 (2H), 7.77 (1H), 8.07-8.28 (2H), 8.33 (1H), 13.45 (1H).

Example 1514-[4-(isopropylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-[4-(isopropylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridinewas isolated as a side product in minor amounts in the preparation ofexample 25.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (6H), 3.55 (1H), 3.81 (8H), 7.38(1H), 7.44 (1H), 7.59 (1H), 7.65 (1H), 7.74-7.94 (2H), 7.95-8.15 (2H),8.35 (1H), 13.43 (1H).

Example 1524-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)(6-fluoropyridin-2-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 2 hours. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 92 mg of crude4-(6-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.19 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:basic conditions) to give 12 mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.35-3.42 (1H), 3.58 (1H),3.73 (1H), 3.84 (1H), 4.06 (1H), 4.16-4.29 (1H), 4.59-4.75 (1H),7.37-7.46 (2H), 7.59-7.67 (2H), 7.72 (1H), 7.82 (1H), 8.26 (1H), 8.36(1H), 13.43 (1H).

Example 1534-(1-ethyl-1H-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(1-ethyl-1H-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 83 mg (0.38 mmol)1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole, 15mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combinded organic phases were filteredusing a Whatman filter and then concentrated to give the crude productthat was used without further purification in the next step.

Step b4-(1-ethyl-1H-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 130 mg of crude4-(1-ethyl-1H-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.28 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:basic conditions) to give 12 mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 1.46 (3H), 3.51-3.64 (1H),3.74 (1H), 3.85 (1H), 3.99-4.26 (4H), 4.62 (1H), 7.38 (1H), 7.51-7.73(2H), 7.88-8.00 (1H), 8.09 (1H), 8.36 (1H), 8.61 (1H), 13.38 (1H).

Example 1541-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}prolinamideStep a1-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}prolinamide

A mixture of 150 mg (0.28 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 110 mg (0.97 mmol) prolinamide in 0.42 mlof MeCN was stirred at 70° C. for 3 hours under argon. After cooling thereaction mixture was diluted with ethyl acetate and washed withsaturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}prolinamide

A solution of 233 mg of crude1-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}prolinamidefrom step a in 2.2 ml of methanol and 0.55 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 18mg (0.05 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.16-1.32 (3H), 1.82-2.10 (3H),2.28-2.36 (1H), 3.24 (1H), 3.45-3.61 (1H), 3.68 (2H), 3.82 (1H),4.01-4.21 (3H), 4.26-4.52 (2H), 6.20 (1H), 7.16 (1H), 7.31 (1H), 7.58(1H), 7.66 (1H), 7.87 (1H), 8.21 (1H), 13.36 (1H).

Example 1553-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pyridin-2-amineStep a3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-amine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 42 mg (0.19 mmol)3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, 15 mg(0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.5 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 90 minutes. After coolingthe reaction mixture was diluted with saturated aqueous sodium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pyridin-2-amine

A solution of 76 mg of crude3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-aminefrom step a in 3.0 ml of methanol and 0.16 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:basic conditions) to give 7 mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.31 (3H), 3.57 (1H), 3.71 (1H), 3.82(1H), 4.06 (1H), 4.21 (1H), 4.57-4.67 (1H), 5.71 (2H), 6.72 (1H), 7.12(1H), 7.29-7.54 (3H), 7.64 (1H), 8.11 (1H), 8.29 (1H), 13.42 (1H).

Example 1562-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 74 mg (0.38 mmol)[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]boronic acid, 15 mg (0.019mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol)of caesium carbonate in 2.0 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 1 hour. Aftercooling the reaction mixture was diluted with saturated aqueous sodiumchloride solution and extracted with ethyl acetate (2×). The combinedorganic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A solution of 107 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-4-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.20 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was dried (MgSO₄), filtered and concentratedto dryness. The residue was purified by preparative HPLC (Autopurifier:basic conditions) to give 7 mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.48 (3H), 3.61 (1H), 3.68-3.81 (1H),3.81-4.00 (2H), 4.05 (1H), 4.20 (1H), 4.50 (1H), 4.89 (2H), 6.79 (1H),7.33 (1H), 7.42 (1H), 7.67-7.79 (2H), 8.08 (1H), 8.47 (1H).

Example 1571-methyl-4-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}piperazin-2-oneStep a1-methyl-4-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperazin-2-one

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 150 mg (0.99 mmol) 1-methylpiperazin-2-onehydrochloride and 0.28 ml (1.99 mmol) of triethylamine in 0.43 ml ofMeCN was stirred at 70° C. overnight under argon. After cooling thereaction mixture was diluted with ethyl acetate and washed withsaturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b1-methyl-4-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}piperazin-2-one

A solution of 207 mg of crude1-methyl-4-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperazin-2-onefrom step a in 2.0 ml of methanol and 0.50 ml of 2N hydrochloric acidwas stirred for 1 h at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 11mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.96 (3H), 3.49 (2H), 3.61 (2H), 3.76(8H), 3.86 (2H), 6.84 (1H), 7.35 (1H), 7.47-7.75 (2H), 8.33 (1H), 13.36(1H).

Example 158 and 1594-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 200 mg (0.38 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 136 mg (0.76 mmol)5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-pyrazole, 31 mg (0.038 mmol)of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 131 mg (0.95 mmol) ofpotassium carbonate in 3.9 ml of acetonitrile and 2.0 ml water wasdegased with argon. Under argon, the reaction mixture was stirred at130° C. for 10 minutes in a microwave oven. After cooling the reactionmixture was diluted with saturated aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to give the crudeproduct that was purified by column chromatography on silica gel(hexane/ethylacetate 40% to ethyl acetate) to give 134 mg of the desiredproduct containing slight impurities.

Step b4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 45 mg (0.10 mmol)2-[(3R)-3-methylmorpholin-4-yl]-4-(1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a, 35 mg (0.20 mmol) of 1-fluoro-2-iodoethane and 66 mg (0.20mmol) of caesium carbonate in 1.0 ml DMF was stirred at 50° C. for 3hours. After cooling, the mixture was diluted with ethyl acetate andwashed with aqueous sodium chloride solution and aqueous sodiumbicarbonate solution. The organic phase was filtered using a Whatmanfilter and concentrated to dryness to give a mixture of the crudeproducts4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridineand4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinethat was used without further purification.

Step c4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 55 mg of a crude misture of4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridineand4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step b in 0.5 ml of methanol and 0.13 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with an aqueous solution of sodium bicarbonate and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 12 mg (0.03mmol) of4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(example 158) and 2 mg (0.005 mmol) of4-[1-(2-fluoroethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine(example 159).

Example 158

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.21-1.37 3H), 3.59 (1H), 3.74 (1H),3.85 (1H), 4.07 (1H), 4.22 (1H), 4.59 (1H), 4.62-4.72 (2H), 4.83 (1H),4.95 (1H), 7.03 (1H), 7.40 (1H), 7.64 (2H), 7.84-8.13 (1H), 8.39 (1H),8.47-8.58 (1H), 13.40 (1H).

Example 159

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 3.58 (1H), 3.72 (1H), 3.82(1H), 4.06 (1H), 4.21 (1H), 4.25-4.39 (2H), 4.53-4.68 (2H), 4.72 (1H),6.60 (1H), 7.23 (1H), 7.42 (1H), 7.53 (1H), 7.65 (1H), 7.77 (1H),8.29-8.36 (1H), 13.32 (1H).

Example 1602-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)ethanolStep a2-[(3R)-3-methylmorpholin-4-yl]-4-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-3-yl}-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 45 mg (0.10 mmol)2-[(3R)-3-methylmorpholin-4-yl]-4-(1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine,25 mg (0.12 mmol) of 2-(2-bromoethoxy)tetrahydro-2H-pyran and 39 mg(0.12 mmol) of caesium carbonate in 0.2 ml DMF was stirred at 70° C. for7 hours. After cooling, the mixture was diluted with ethyl acetate andwashed with aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and concentrated to dryness to give amixture of the crude products that was used without furtherpurification.

Step b2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)ethanol

A solution of 52 mg crude2-[(3R)-3-methylmorpholin-4-yl]-4-{1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-3-yl}-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 0.8 ml of methanol and 0.21 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with an aqueous solution of sodium bicarbonate and extractedwith ethyl acetate and THF (2×). The combined organic phases werefiltered using a Whatman filter and concentrated to dryness. The residuewas purified by preparative HPLC (Autopurifier: basic conditions) togive 11 mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 3.35-3.41 (1H), 3.53-3.63(1H), 3.70-3.79 (1H), 3.85 (3H), 4.00-4.10 (1H), 4.17-4.24 (1H), 4.31(2H), 4.63-4.73 (1H), 5.00 (1H), 6.98 (1H), 7.40 (1H), 7.62 (2H), 7.94(1H), 8.38 (1H), 8.56 (1H), 13.41 (1H).

Example 1612-methyl-1-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)propan-2-olStep a2-methyl-1-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)propan-2-ol

In a closed vessel under argon, a mixture of 50 mg (0.11 mmol)2-[(3R)-3-methylmorpholin-4-yl]-4-(1H-pyrazol-5-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine,16 mg (0.22 mmol) of 2,2-dimethyloxirane and 23 mg (0.17 mmol) ofpotassium carbonate in 0.5 ml DMF was stirred at 130° C. in a microwaveoven for 10 minutes. After cooling, 31 mg (0.29 mmol) of2,2-dimethyloxirane was added and the mixture was stirred at 130° C. ina microwave oven for 10 minutes. After cooling, the mixture was dilutedwith ethyl acetate and washed with water. The organic phase was filteredusing a Whatman filter and concentrated to dryness to give a mixture ofthe crude products that was used without further purification.

Step b2-methyl-1-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)propan-2-ol

A solution of 30 mg crude2-methyl-1-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-1H-pyrazol-1-yl)propan-2-olfrom step a in 1.5 ml of methanol and 0.06 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with an aqueous solution of sodium bicarbonate and extractedwith ethyl acetate and THF (2×). The combined organic phases werefiltered using a Whatman filter and concentrated to dryness. The residuewas purified by preparative HPLC (Autopurifier: basic conditions) togive 8 mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.17 (6H), 1.30 (3H), 3.50-3.67 (1H),3.74 (1H), 3.85 (1H), 3.99-4.15 (1H), 4.15-4.40 (3H), 4.68 (1H), 4.81(1H), 7.00 (1H), 7.40 (1H), 7.54-7.70 (2H), 7.89 (1H), 8.37 (1H), 8.56(1H), 13.40 (1H).

Example 1624-[(2R)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(2R)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 103 mg (1.02 mmol) (2R)-2-methylmorpholinehydrochloride and 0.14 ml (1.02 mmol) trimethylamine in 0.5 ml of MeCNwas stirred at 70° C. overnight under argon. After cooling the reactionmixture was diluted with ethyl acetate and washed with saturated aqueoussodium chloride solution. The organic phase was filtered using a Whatmanfilter and then concentrated to give the crude product that was usedwithout further purification in the next step.

Step b4-[(2R)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 178 mg of crude4-[(2R)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 8.6 ml of methanol and 0.38 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 64mg (0.17 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.16 (3H), 2.57-2.69 (1H), 2.87 (1H),3.32-3.41 (2H), 3.71 (4H), 3.77 (4H), 3.81-3.97 (3H), 6.81 (1H), 7.33(1H), 7.59 (1H), 7.63 (1H), 8.31 (1H), 13.32 (1H).

Example 1634-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)(5-fluoropyridin-2-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 150 minutes.After cooling the reaction mixture was diluted with saturated aqueousammonium chloride solution and extracted with ethyl acetate (2×). Thecombined organic phases were filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 106 mg of crude4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.22 ml of 2N hydrochloric acidwas stirred for 2 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter andconcentrated to dryness. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 3 mg (0.01 mmol) of the desiredproduct.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.26-1.39 (3H), 3.53-3.65 (2H), 3.73(1H), 3.84 (1H), 4.06 (1H), 4.24 (1H), 4.67 (1H), 7.42 (1H), 7.44-7.53(1H), 7.60 (1H), 7.62-7.67 (1H), 7.68-7.74 (1H), 7.87-8.13 (2H),8.28-8.44 (1H), 8.84 (1H), 13.20 (1H).

Example 1642-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 52 mg (0.38 mmol)(6-methylpyridin-2-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 113 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 5.4 ml of methanol and 0.24 ml of 2N hydrochloric acidwas stirred for 2 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter andconcentrated to dryness. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desiredproduct.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.30 (3H), 2.57-2.63 (3H), 3.53-3.64(1H), 3.73 (1H), 3.80-3.89 (1H), 4.06 (1H), 4.22 (1H), 4.66 (1H), 7.44(2H), 7.55 (1H), 7.58-7.68 (2H), 7.72 (1H), 7.93 (1H), 8.33 (1H), 13.42(1H).

Example 1652-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 52 mg (0.38 mmol)(3-methylpyridin-2-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and then concentrated togive the crude product that was used without further purification in thenext step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 113 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 4.3 ml of methanol and 0.19 ml of 2N hydrochloric acidwas stirred for 2 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter andconcentrated to dryness. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desiredproduct.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.29 (d, 3H), 2.13 (s, 3H), 3.57 (d,1H), 3.67-3.79 (m, 1H), 3.79-3.90 (m, 1H), 4.05 (d, 1H), 4.15-4.30 (m,2H), 4.61 (1H), 6.96 (1H), 7.38-7.57 (3H), 7.65 (1H), 7.89 (1H), 8.27(1H), 8.59 (1H), 13.43 (1H).

Example 166N-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phenyl)acetamideStep aN-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)acetamide

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 68 mg (0.38 mmol) (2-acetamidophenyl)boronicacid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexwith dichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) ofcaesium carbonate in 1.4 ml of dioxane was degased with argon. Underargon, the reaction mixture was stirred at 110° C. for 7 hours. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith aqueous sodium chloride solution. The organic phase was filteredusing a Whatman filter and then concentrated to give the crude productthat was used without further purification in the next step.

Step bN-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phenyl)acetamide

A solution of 164 mg of crudeN-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)acetamidefrom step a in 1.5 ml of methanol and 0.37 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with ethyl acetate and washed with aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter andconcentrated to dryness. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 11 mg (0.03 mmol) of thedesired product.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.32 (3H), 1.71 (3H), 3.50-3.64 (1H),3.64-3.78 (1H), 3.78-3.92 (1H), 4.07 (1H), 4.23 (1H), 4.59 (1H), 7.02(1H), 7.20-7.47 (4H), 7.47-7.60 (1H), 7.65 (1H), 7.74 (1H), 8.24 (1H),9.16 (1H), 12.82 (1H).

Example 1673-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pyridin-2-olStep a3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-ol

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)(2-hydroxypyridin-3-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}pyridin-2-ol

A solution of 96 mg of crude3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}pyridin-2-olfrom step a in 5.1 ml of methanol and 0.20 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 2 mg (0.005mmol) of the desired product.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.30 (3H), 3.57 (1H), 3.71 (1H), 3.82(1H), 4.04 (1H), 4.18 (1H), 4.62 (1H), 6.39 (1H), 7.27 (1H), 7.40 (2H),7.50-7.75 (3H), 8.28 (1H), 12.05 (1H), 13.39 (1H).

Example 1682-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phenyl)propan-2-olStep a2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)propan-2-ol

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 53 mg (0.38 mmol)(2-hydroxypyridin-3-yl)boronic acid, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 247 mg (0.76 mmol) of caesiumcarbonate in 1.4 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 2 hours. After cooling thereaction mixture was diluted aqueous sodium chloride solution andextracted with ethyl acetate (2×). The combined organic phases werefiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}phenyl)propan-2-ol

A solution of 96 mg of crude2-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}phenyl)propan-2-olfrom step a in 5.1 ml of methanol and 0.20 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with aqueous sodium chloride solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 2 mg (0.005mmol) of the desired product.

¹H-NMR (400 MHz, CDCl₃): δ [ppm]=1.30 (3H), 3.57 (1H), 3.71 (1H), 3.82(1H), 4.04 (1H), 4.18 (1H), 4.62 (1H), 6.39 (1H), 7.27 (1H), 7.40 (2H),7.50-7.75 (3H), 8.28 (1H), 12.05 (1H), 13.39 (1H).

Example 1694-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 122 mg (0.99 mmol)5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine in 0.4 ml of MeCN was stirredat 70° C. for 90 minutes under argon. After cooling the reaction mixturewas diluted with ethyl acetate and washed with saturated aqueous sodiumchloride solution. The organic phase was filtered using a Whatman filterand then concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 200 mg of crude4-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.9 ml of methanol and 0.47 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 5mg (0.01 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.66 (2H), 3.72-3.87 (8H), 4.27-4.40(2H), 4.47 (2H), 6.85-7.05 (2H), 7.23 (1H), 7.36 (1H), 7.62 (1H), 7.68(1H), 8.34 (1H), 13.37 (1H).

Example 1704-[(2S)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(2S)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 103 mg (1.02 mmol) (2S)-2-methylmorpholinein 0.5 ml of MeCN was stirred at 70° C. overnight under argon. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-[(2S)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 146 mg of crude4-[(2S)-2-methylmorpholin-4-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 7.0 ml of methanol and 0.31 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 62mg (0.16 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.16 (3H), 2.57-2.69 (1H), 2.87 (1H),3.32-3.41 (2H), 3.71 (4H), 3.77 (4H), 3.81-3.97 (3H), 6.81 (1H), 7.33(1H), 7.59 (1H), 7.63 (1H), 8.31 (1H), 13.32 (1H).

Example 1714-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 69 mg (0.38 mmol)trans-1-methyl-cyclopropyl-2-boronic ester, 15 mg (0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b4-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 113 mg of crude4-[(trans)-2-methylcyclopropyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 3.0 ml of methanol and 0.26 ml of 2N hydrochloric acidwas stirred for 3 hours at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 8 mg (0.02mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.86-0.94 (1H), 1.19-1.28 (5H),1.28-1.34 (3H), 2.14-2.24 (1H), 3.22-3.32 (1H), 3.54 (1H), 3.69 (1H),3.81 (1H), 4.03 (1H), 4.09-4.24 (1H), 4.49-4.77 (1H), 7.00 (1H), 7.37(1H), 7.61 (1H), 7.93 (1H), 8.41 (1H), 13.38 (1H).

Example 1724-(difluoromethoxy)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(difluoromethoxy)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 100 mg (0.25 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol,66 mg (0.51 mmol) chlorodifluoroacetic acid and 42 mg (0.30 mmol) ofpotassium carbonate in 0.9 ml of DMF and 0.9 ml water was degased withargon. Under argon, the reaction mixture was stirred at 120° C. for 90minutes. After cooling the reaction mixture was diluted with ethylacetate and washed with aqueous sodium chloride solution. The organicphase was filtered using a Whatman filter and then concentrated to givethe crude product that was used without further purification in the nextstep.

Step b4-(difluoromethoxy)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 71 mg of crude4-(difluoromethoxy)-2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 0.7 ml of methanol and 0.18 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with aqueous bicarbonate solution and extracted with ethylacetate (2×). The combined organic phases were filtered using a Whatmanfilter and concentrated to dryness. The residue was purified bypreparative HPLC (Autopurifier: basic conditions) to give 7 mg (0.02mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.29 (3H), 3.56 (1H), 3.66-3.79 (1H),3.84 (1H), 4.05 (1H), 4.15 (d, 1H), 4.58 (1H), 7.16 (1H), 7.39 (1H),7.62 (1H), 7.66-7.74 (2H), 8.40 (1H), 13.40 (1H).

Example 1732-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]propan-2-olStep a2-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}propan-2-ol

0.24 ml (0.71 mmol) of a 3.0 M solution of methylmagnesium bromide indiethylether was added dropwise to a stirred solution of 100 mg (0.24mmol) methyl2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine-4-carboxylatein 4.0 ml of THF at 0° C. The mixture was stirred at 0° C. for 30minutes and then the icebath was removed and the mixture was stirred atroom temperature overnight. The mixture was diluted with a saturatedaqueous solution of ammonium chloride and extracted with ethyl acetate(2×). The combined organic phases were filtered using a Whatman filterand then concentrated to give the crude product that was used withoutfurther purification in the next step.

Step b2-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]propan-2-ol

A solution of 80 mg of crude2-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}propan-2-olfrom step a in 2.0 ml of methanol and 0.19 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were dried (MgSO₄),filtered and concentrated to dryness to give 34 mg (0.09 mmol) of thedesired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.69 (6H), 3.73 (4H), 3.77-3.93 (4H),5.60 (1H), 7.35 (1H), 7.46 (1H), 7.61 (1H), 8.28-8.45 (2H), 13.35 (1H).

Example 1742-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 153 mg (1.02 mmol)3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1:1) and 0.14 ml (1.02mmol) triethylamine in 0.5 ml of MeCN was stirred at 70° C. for 72 hoursunder argon. After cooling the reaction mixture was diluted with DCM andwashed with saturated aqueous sodium chloride solution. The organicphase was filtered using a Whatman filter and then concentrated to givethe crude product that was used without further purification in the nextstep.

Step b2-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 152 mg of crude2-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 7.2 ml of methanol and 0.32 ml of 2N hydrochloric acidwas stirred overnight at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 12mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.92 (3H), 3.58-3.72 (6H), 3.72-3.86(4H), 3.94 (2H), 4.15 (2H), 6.70 (1H), 7.34 (1H), 7.60 (1H), 7.71 (1H),8.31 (1H), 13.34 (1H).

Example 1752-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(pyrrolidin-1-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-4-(pyrrolidin-1-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 75 mg (0.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 35 mg (0.50 mmol) pyrrolidine in 0.21 mlof MeCN was stirred at 70° C. for 90 minutes under argon. After coolingthe reaction mixture was diluted with ethyl acetate and washed withsaturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(pyrrolidin-1-yl)-1,7-naphthyridine

A solution of 10 mg of crude2-[(3R)-3-methylmorpholin-4-yl]-4-(pyrrolidin-1-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 0.5 ml of methanol and 0.02 ml of 2N hydrochloric acidwas stirred overnight at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 2mg (0.005 mmol) of the desired product.

¹H-NMR (400 MHz, CDCl3): δ [ppm]=1.47 (3H), 2.20 (4H), 3.55 (1H),3.66-3.94 (7H), 4.04 (1H), 4.16-4.37 (2H), 5.75 (1H), 7.12 (1H), 7.77(1H), 7.90 (1H), 8.53 (1H).

Example 1764-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]piperazin-2-oneStep a4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperazin-2-one

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 99 mg (0.99 mmol) piperazin-2-one in 0.4ml of MeCN was stirred at 70° C. for 3 hours under argon. After coolingthe reaction mixture was diluted with ethyl acetate and washed withsaturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]piperazin-2-one

A solution of 182 mg of crude4-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}piperazin-2-onefrom step a in 1.8 ml of methanol and 0.45 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 32mg (0.08 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.39-3.45 (2H), 3.45-3.55 (2H),3.64-3.88 (10H), 6.84 (1H), 7.35 (1H), 7.63 (2H), 8.11 (1H), 8.32 (1H),13.36 (1H).

Example 1774-(dimethylphosphoryl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(dimethylphosphoryl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 36 mg (0.33 mmol) dimethylphosphinoxide, 34mg (0.029 mmol tetrakis(triphenylphosphine)palladium(0) and 0.06 ml(0.44 mmol) of triethylamine in 0.9 ml of acetonitrile was degased withargon. Under argon, the reaction mixture was stirred at 90° C. for 3hours. After cooling the reaction mixture was diluted with ethyl acetateand washed with aqueous chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b4-(dimethylphosphoryl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 210 mg of crude4-(dimethylphosphoryl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.2 ml of methanol and 0.55 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: basic conditions) to give 21 mg (0.06mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.88 (3H), 1.92 (3H), 3.78 (8H), 7.35(1H), 7.55-7.79 (2H), 8.33-8.51 (2H), 13.37 (1H).

Example 1784-[(trans)-2,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(trans)-2,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 113 mg (0.99 mmol)(trans)-2,5-dimethylpiperazine in 0.4 ml of MeCN was stirred at 70° C.for 3 hours under argon. After cooling the reaction mixture was dilutedwith ethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-[(trans)-2,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 117 mg of crude4-[(trans)-2,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.1 ml of methanol and 0.28 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 3mg (0.008 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.81-0.95 (3H), 0.95-1.06 (3H),2.24-2.40 (1H), 2.63-2.75 (1H), 3.02-3.21 (4H), 3.67-3.77 (4H),3.77-3.85 (4H), 7.12 (1H), 7.36 (1H), 7.62 (1H), 7.79 (1H), 8.24 (1H),8.36 (1H).

Example 1794-[(cis)-3,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-[(cis)-3,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 113 mg (0.99 mmol)(cis)-2,6-dimethylpiperazine in 0.4 ml of MeCN was stirred at 70° C. for90 minutes under argon. After cooling the reaction mixture was dilutedwith ethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-[(cis)-3,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 189 mg of crude4-[(cis)-3,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 1.8 ml of methanol and 0.46 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 51mg (0.13 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.03 (6H), 2.30-2.42 (2H), 2.94-3.16(2H), 3.35 (2H), 3.63-3.74 (4H), 3.74-3.87 (4H), 6.75 (1H), 7.34 (1H),7.59 (2H), 8.28-8.35 (1H), 13.33 (1H).

Example 1801-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]-3-(trifluoromethyl)azetidin-3-olStep a1-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-3-(trifluoromethyl)azetidin-3-ol

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 182 mg (1.02 mmol)3-(trifluoromethyl)azetidin-3-ol hydrochloride (1:1) and 0.14 ml (1.02mmol) trimethylamine in 0.5 ml of MeCN was stirred at 70° C. for 90minutes under argon. After cooling the reaction mixture was diluted withethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]-3-(trifluoromethyl)azetidin-3-ol

A solution of 156 mg of crude1-{2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}-3-(trifluoromethyl)azetidin-3-olfrom step a in 7.0 ml of methanol and 0.31 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 6mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.53-3.71 (4H), 3.71-3.84 (4H), 4.30(2H), 4.64 (2H), 6.23 (1H), 7.30 (1H), 7.47 (1H), 7.54-7.68 (2H), 8.22(1H), 13.33 (1H).

Example 181 methyl hydrogen{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}phosphonate

A mixture of 33 mg (0.07 mmol) of dimethyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}phosphonateand 0.14 ml (0.28 mmol) aqueous 2N sodium hydroxide solution in 0.14 mlof MeOH was stirred at 70° C. for 4 hours. The pH was adjusted to 6 bythe addition of aqueous sodium bicarbonate solution and the mixture wasextracted with THF (3×). The combined organic phases were filtered usinga Whatman filter and concentrated. The residue was purified bypreparative HPLC (Autopurifier: acidic conditions) to give 1 mg (0.002mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.56-3.63 (8H), 3.80 (3H), 7.40 (1H),7.41 (1H), 7.52 (1H), 7.65 (1H), 7.69 (2H), 7.89 (3H), 8.33 (1H)

Example 1824-(4-methylpiperazin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(4-methylpiperazin-1-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate and 100 mg (0.99 mmol) 1-methylpiperazine in0.4 ml of MeCN was stirred at 70° C. for 90 minutes under argon. Aftercooling the reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium chloride solution. The organic phase wasfiltered using a Whatman filter and then concentrated to give the crudeproduct that was used without further purification in the next step.

Step b2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-1,7-naphthyridine

A solution of 204 mg of crude2-(morpholin-4-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.0 ml of methanol and 0.51 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 7mg (0.02 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.30 (3H), 2.61 (4H), 3.18 (4H),3.62-3.75 (4H), 3.78 (4H), 6.81 (1H), 7.35 (1H), 7.53-7.69 (2H), 8.32(1H), 13.35 (1H).

Example 1832-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-1,7-naphthyridineStep a2-(morpholin-4-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 153 mg (1.00 mmol)(3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride and 0.14 ml(1.00 mol) of triethylamine in 0.4 ml of MeCN was stirred at 70° C. for3 hours under argon. After cooling the reaction mixture was diluted withethyl acetate and washed with saturated aqueous sodium chloridesolution. The organic phase was filtered using a Whatman filter and thenconcentrated to give the crude product that was used without furtherpurification in the next step.

Step b4-(4-methylpiperazin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 176 mg of crude2-(morpholin-4-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 8.2 ml of methanol and 0.37 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 13mg (0.03 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.30 (3H), 2.61 (4H), 3.18 (4H),3.62-3.75 (4H), 3.78 (4H), 6.81 (1H), 7.35 (1H), 7.53-7.69 (2H), 8.32(1H), 13.35 (1H).

Example 1844-(3-methoxy-3-methylazetidin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(3-methoxy-3-methylazetidin-1-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 137 mg (0.99 mmol)3-methoxy-3-methylazetidine hydrochloride and 0.28 ml (1.99 mmol)trimethylamine in 0.4 ml of MeCN was stirred at 70° C. for 90 minutesunder argon. After cooling the reaction mixture was diluted with ethylacetate and washed with saturated aqueous sodium chloride solution. Theorganic phase was filtered using a Whatman filter and then concentratedto give the crude product that was used without further purification inthe next step.

Step b4-(3-methoxy-3-methylazetidin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 225 mg of crude4-(3-methoxy-3-methylazetidin-1-yl)-2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 2.3 ml of methanol and 0.56 ml of 2N hydrochloric acidwas stirred for 1 hour at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 3mg (0.01 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.52 (3H), 3.25 (3H), 3.59-3.71 (4H),3.71-3.85 (4H), 4.17 (2H), 4.27 (2H), 6.11 (1H), 7.31 (1H), 7.59 (1H),7.65 (1H), 8.22 (1H), 13.36 (1H).

Example 1852-(morpholin-4-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-(morpholin-4-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

A mixture of 150 mg (0.29 mmol) of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 139 mg (1.00 mmol)(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 0.14 ml (1.02mmol) trimethylamine in 0.4 ml of MeCN was stirred at 70° C. overnightunder argon. After cooling the reaction mixture was diluted with ethylacetate and washed with saturated aqueous sodium chloride solution. Theorganic phase was filtered using a Whatman filter and then concentratedto give the crude product that was used without further purification inthe next step.

Step b2-(morpholin-4-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

A solution of 172 mg of crude2-(morpholin-4-yl)-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridinefrom step a in 8.3 ml of methanol and 0.37 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to dryness. The residue waspurified by preparative HPLC (Autopurifier: basic conditions) to give 39mg (0.10 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.91 (1H), 2.03 (1H), 3.38 (1H),3.56-3.72 (4H), 3.72-3.86 (5H), 3.89-4.14 (2H), 4.64 (1H), 4.78 (1H),6.44 (1H), 7.29 (1H), 7.58 (1H), 7.70 (1H), 8.20 (1H), 13.32 (1H).

Example 1862-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-ol

A suspension of 2310 mg (8.3 mmol) of8-chloro-2-(3-methylmorpholin-4-yl)-1,7-naphthyridin-4-ol, 3000 mg (12.4mmol) (1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)boronicacid, 1348 mg (1.7 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 4251 mg (13.0 mmol) of caesiumcarbonate in 69 ml of dioxane was degased with argon. Under argon, thereaction mixture was stirred at 110° C. for 1 hour. After cooling thereaction mixture was diluted with aqueous sodium chloride solution andextracted with ethyl acetate (3×). The combined organic phases werefiltered using a Whatman filter and then concentrated. The residue waspurified by column chromatography (gradient from 100% Hex to 100% EtOAc)to give 1710 mg (3.9 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=−0.35-0.27 (9H), 0.47-0.61 (2H), 1.18(3H), 3.06-3.29 (3H), 3.46 (1H), 3.63 (1H), 3.74 (1H), 3.95 (2H), 4.32(1H), 5.81 (1H), 5.88 (1H), 6.59 (1H), 6.98 (1H), 7.63 (1H), 7.78 (1H),8.32 (1H), 11.49 (1H).

Step b2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yltrifluoromethanesulfonate

A mixture of 1710 mg (3.9 mmol)2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-ol,1549 mg (4.3 mmol)1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamideand 1.35 ml (7.7 mmol) of N,N-diisopropyethylamin in 22 ml of DCM wasstirred at room temperature for 2 hours. The mixture was concentratedand the residue was purified by column chromatography (gradient from100% Hex to hexane/EtOAc 50%) to give 1870 mg (3.3 mmol) of the desiredproduct.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=−0.37 (9H), 0.43-0.64 (2H), 1.23(3H), 3.13-3.30 (3H), 3.49 (1H), 3.64 (1H), 3.79 (1H), 3.96-4.03 (1H),4.14 (1H), 4.48 (1H), 5.82 (1H), 5.89 (1H), 7.05 (1H), 7.64 (1H), 7.68(1H), 7.76 (1H), 8.54 (1H).

Step c methyl2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridine-4-carboxylate

In an autoclave, a mixture of 1800 mg (3.14 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 133 mg (0.31 mmol)1,3-bis(diphenylphosphino)propane, 70 mg (0.31 mmol) palladium(II)acetate and 0.9 ml triethylamine (6.3 mmol) in 22 ml of DMF and 12 ml ofmethanol was purged with carbon monoxide at room temperature. Theautoclave was pressured with carbonmonoxide to 13.7 bar and the mixturewas stirred at room temperature for 30 minutes. The autoclave wasdepressurized and then pressured with carbon monoxide to 16.1 bar. Themixture was stirred at 80° C. for 24 hours. The autoclave wasdepressurized and after cooling, the mixture was diluted with ethylacetate and washed with aqueous sodium chloride solution. The organicphase was dried (Na₂SO₄), filtered and concentrated. The residue waspurified by column chromatography (gradient from 100% Hex to 100% EtOAc)to give 720 mg (1.49 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=−0.48-0.30 (9H), 0.42-0.61 (2H), 1.22(3H), 3.20 (3H), 3.48 (1H), 3.54-3.68 (1H), 3.75 (1H), 3.88-4.05 (4H),4.10 (1H), 4.50 (1H), 5.78 (1H), 5.85 (1H), 6.96 (1H), 7.66 (1H), 7.87(1H), 8.19 (1H), 8.46 (1H).

Step d{2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}methanol

3.0 ml (3.00 mmol) of a 1M solution of DIBAL in toluene was added to asolution of 720 mg (1.49 mmol) of methyl2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridine-4-carboxylatein 17 ml of dry THF at room temperature and the mixture was stirred at70° C. for 4 hours. After cooling, the mixture was diluted with 25 ml ofa saturated solution of ammonium chloride and stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate andfiltered using a Whatman filter. The organic phase was concentrated andthe residue was purified by column chromatography (gradient from 100%Hex to 100% EtOAc) to give 405 mg (0.89 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=−0.37-0.25 (9H), 0.39-0.62 (2H),1.13-1.31 (3H), 3.12-3.28 (3H), 3.48 (1H), 3.63 (1H), 3.77 (1H), 3.98(1H), 4.11 (1H), 4.47 (1H), 4.93 (2H), 5.65 (1H), 5.80 (1H), 5.86 (1H),6.96 (1H), 7.45 (1H), 7.64 (1H), 7.72 (1H), 8.38 (1H).

Step e4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridineand4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.05 ml (0.66 mmol) thiony chloride was added to a stirred solution of{2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}methanolin 33 ml of dry DMF at 0° C. The mixture was stirred at 5° C. for 1hour. Toluene was added and the mixture was concentrated to give a crudemixture of4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridineand4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine.

Step f2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridineand2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

0.56 ml (1.71 mmol) of an aqueous solution of sodium methanethiolate(21%) was added to 184 mg of a crude mixture of4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridineand4-(chloromethyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridinefrom step e in 4.3 ml of acetone at room temperature. The mixture wasstirred at room temperature for 150 minutes before it was diluted withethyl acetate and washed with an aqueous solution of sodium chloride.The organic phase was filtered using a Whatman filter and concentrated.The residue was purified by preparative HPLC (Autopurifier: basicconditions) to give 33 mg (0.07 mmol)2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridineand 32 mg (0.09 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine.

2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridine

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=−0.14-0.02 (9H), 0.86 (2H), 1.24(3H), 2.02 (3H), 3.26 (1H), 3.53 (1H), 3.60 (2H), 3.64-3.73 (1H), 3.77(1H), 3.91-4.05 (1H), 4.10 (2H), 4.18 (1H), 4.53 (1H), 5.50 (2H), 7.17(1H), 7.39 (1H), 7.81 (1H), 7.95 (1H), 8.35 (1H).

2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfanyl)methyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.20-1.36 (3H), 2.02 (3H), 3.32 (1H),3.52-3.67 (1H), 3.73 (1H), 3.84 (1H), 3.96-4.23 (4H), 4.55 (1H), 7.38(1H), 7.47 (1H), 7.62 (1H), 7.83 (1H), 8.37 (1H), 13.38 (1H).

Example 187N,N-dimethyl-5-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin-2-amine

Example 187 was prepared using Automated Medicinal Chemistry (seeexamples 346-437). However, initial purity was not sufficient fortesting and therefore the sample had to be purified by a secondpreparative HPLC (Autopurifier: basic conditions) to give 1 mg (0.002mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.13 (6H), 3.80 (8H), 6.83 (1H),7.31-7.49 (2H), 7.53 (1H), 7.64 (1H), 7.77 (1H), 8.18-8.39 (2H), 13.42(1H).

Example 1884-(2-methylpyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

Example 187 was prepared using Automated Medicinal Chemistry (seeexamples 346-437). However, initial purity was not sufficient fortesting and therefore the sample had to be purified by a secondpreparative HPLC (Autopurifier: basic conditions) to give 0.7 mg (0.002mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.60 (3H), 3.80 (8H), 7.40 (2H), 7.43(1H), 7.48 (1H), 7.54 (1H), 7.65 (1H), 8.34 (1H), 8.64 (1H), 13.44 (1H).

Example 1891-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}cyclohexanolStep a1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}cyclohexanol

0.23 ml (0.12 mmol) of a solution of 0.5M pentamethylenebis(magnesiumbromide) in THF was added to a solution of 56 mg (0.12 mmol) methyl2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridine-4-carboxylatein 3.0 ml of THF at 0° C. under argon. The mixture was stirred at 0° C.for 30 minutes and then 1 hour at room temperature. Additional 0.12 ml(0.06 mmol) of the solution of 0.5M pentamethylenebis(magnesium bromide)in THF was added and the mixture was stirred for 150 minutes at roomtemperature. The mixture was diluted with aqueous ammonium chloridesolution and extracted with ethyl acetate (2×). The combined organicphases were filtered using a Whatman filter and concentrated. Theresidue was purified by column chromatography (gradient from 100% Hexhexane/EtOAc 50%) to give 26 mg (0.05 mmol) the desired product.

Step b1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}cyclohexanol

0.04 ml (0.08 mmol) of a 2N aqueous hydrogen chloride solution was addedto a solution of 20 mg (0.038 mmol) of1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}cyclohexanolfrom step a in 0.4 ml of dioxane. The mixture was stirred at roomtemperature for 7 hours. The mixture was diluted with aqueous sodiumchloride solution and extracted with ethyl acetat (2×) and DCM (1×). Thecombined organic phases were filtered using a Whatman filter andconcentrated. The residue was purified by preparative HPLC(Autopurifier: basic conditions) to give 4 mg (0.01 mmol) of the desiredproduct.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.25 (3H), 1.41-1.57 (2H), 1.57-1.68(1H), 1.70-1.84 (1H), 1.96-2.11 (2H), 3.31 (1H), 3.56 (1H), 3.71 (1H),3.82 (1H), 4.05 (1H), 4.12 (1H), 4.53 (1H), 4.89-5.01 (2H), 5.09-5.29(1H), 5.61 (1H), 5.77 (1H), 7.36 (1H), 7.49 (1H), 7.60 (1H), 7.77 (1H),8.34 (1H), 13.36 (1H).

Example 1905-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}anilineStep a2-fluoro-6-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}aniline

A suspension of 100 mg (0.19 mmol) of2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate, 90 mg (0.38 mmol)2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 15 mg(0.019 mmol) of[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1, Pd(dppf)Cl₂) and 65 mg (0.47 mmol) of potassiumcarbonate in 2.0 ml of acetonitrile and 1.0 ml water was degased withargon. Under argon, the reaction mixture was stirred at 130° C. for 10minutes in a microwave oven. After cooling the reaction mixture wasdiluted with saturated aqueous sodium chloride solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and then concentrated to give the crude product thatwas used without further purification in the next step.

Step b2-fluoro-6-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}aniline

A solution of 156 mg of crude2-fluoro-6-{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}anilinefrom step a in 5.8 ml of methanol and 0.30 ml of 2N hydrochloric acidwas stirred for 90 minutes at room temperature. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate solution and extractedwith ethyl acetate (2×). The combined organic phases were filtered usinga Whatman filter and concentrated to dryness. The residue was purifiedby preparative HPLC (Autopurifier: acidic conditions) to give 2 mg(0.005 mmol) of the desired product.

¹H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.22-1.40 (3H), 3.51-3.64 (1H), 3.71(1H), 3.82 (1H), 4.05 (1H), 4.21 (1H), 4.54-4.70 (1H), 4.89 (2H),6.62-6.76 (1H), 6.90 (1H), 6.97-7.26 (2H), 7.39 (1H), 7.44 (1H),7.55-7.74 (1H), 8.28 (1H), 13.42 (1H).

Example 191(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)cyanamideStep a4-[4-(methylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-{1-[(2)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine

4-[(2-(Morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulphoximide(1.00 g, 1.52 mmol) was solubilised in a solution of NaOMe (30% solutionin MeOH, 25 mL). the reaction was stirred at 60° C. for 3 h. Thereaction mixture was concentrated under reduced pressure and dilutedwith DCM and H₂O. The aqueous phase was extracted two times with DCM.The combined organic phases were washed with brine, dried (siliconfilter) and concentrated under reduced pressure. The titled compound wasobtain in quantitative yield without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=1.40-1.66 (m, 3H), 1.99 (br. s., 2H),2.30-2.47 (m, 1H), 3.17 (s, 3H), 3.22-3.30 (m, 1H), 3.72 (s, 8H), 4.35(s, 1H), 5.75 (s, 1H), 6.06-6.12 (m, 1H), 6.93 (d, 1H), 7.41 (d, 1H),7.50 (s, 1H), 7.64 (d, 1H), 7.82 (d, 2H), 8.13 (d, 2H), 8.38 (d, 1H).

Step b(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)cyanamide

4-[4-(Methylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-{1-[(2)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine(200 mg, 0.39 mmol) was solubilised in DCM (6 mL). DMAP (51 mg, 0.42mmol) and BrCN (82 mg, 0.77 mmol, 3M solution) were added sequentially.The reaction was stirred at rt for 16 h. The reaction mixture wasconcentrated under reduced pressure and diluted with MeOH. Thesuspension was filtered, washed with MeOH and dried under reducedpressure. The crude solid (74 mg) was then solubilized in DCM (2 mL) and3M HCl (1.5 mL) was added. The reaction was stirred for 1 h at rt. Thereaction was quenched by addition of sat. bicarbonate and the solid wasfiltered and dried. The title compound was obtained without furtherpurification in (60 mg).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.76-3.85 (m, 11H), 7.33 (d, 1H),7.43 (br. s, 1H), 7.60-7.68 (m, 2H), 8.00 (d, 2H), 8.26 (d, 2H), 8.36(d, 1H), 13.42 (br. s, 1H).

Example 1921-ethyl-3-(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)ureaStep a(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)cyanamide

4-[4-(Methylsulfonimidoyl)phenyl]-2-(morpholin-4-yl)-8-{1-[(2)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine(100 mg, 0.19 mmol) was solubilised in DCM (6 mL). Triethylamine (39 mg,0.39 mmol) and ethyl isocyanate (27 mg, 0.39 mmol) were added. Thereaction was stirred for 16 h at rt and triethylamine (195 mg, 3.89mmol) and ethyl isocyanate (135 mg, 1.95 mmol) were added. The reactionwas stirred for 16 h at rt and concentrated under reduced pressure. Thecrude material was solubilized in DMF (6 mL) and triethylamine (195 mg,3.89 mmol) and ethyl isocyanate (135 mg, 1.95 mmol) were added. Thereaction was stirred for 48 h at 60° C. The reaction was diluted withwater and extracted with DCM. The organic phase was dried (siliconfilter) and concentrated under reduced pressure. The crude material waspurified by flash chromatography (100% Hexane to 100% AcOEt to 20%MeOH). The titled compound was obtained in 78% yield (93 mg). ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm]=0.99 (t, 3H), 1.40-1.66 (m, 3H), 1.99 (s,2H), 2.34-2.45 (m, 1H), 2.90-3.04 (m, 2H), 3.23-3.29 (m, 1H), 3.45 (s,3H), 3.72 (s, 9H), 6.09 (dd, 1H), 6.94 (d, 1H), 7.00 (t, 1H), 7.41 (d,1H), 7.53 (s, 1H), 7.64 (d, 1H), 7.87 (d, 2H), 8.11 (d, 2H), 8.39 (d,1H).

Step b1-ethyl-3-(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)urea

(Methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}oxido-λ⁶-sulfanylidene)cyanamide(93 mg, 46 mmol) was solubilized in DCM (3 mL) and 3M HCl (2 mL) wasadded. The reaction was stirred 16 h at rt and then quenched with satNaHCO3. The aqueous phase was extracted with DCM and the organic phasewas dried (silicon filter) and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography (100% Hexaneto 100% AcOEt to 20% MeOH) and the titled compound was obtained in 85%yield (68 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.99 (t, 3H),2.90-3.03 (m, 2H), 3.45 (s, 3H), 3.80 (s, 8H), 7.00 (t, 1H), 7.35 (d,1H), 7.43 (br. s, 1H), 7.57 (s, 1H), 7.65 (br. s, 1H), 7.86 (d, 2H),8.11 (d, 2H), 8.35 (d, 1H), 13.37-13.47 (m, 1H).

Example 1933-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)propan-1-amine

Tert-butyl[3-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)propyl]carbamate(80 mg, 0.15 mmol) was solubilised in DCM (2 mL) and TFA (0.22 mL, 2.9mmol) was added. The reaction was stirred 2 h at rt and quenched withsat. NaHCO₃. The aqueous phase was extracted with DCM and the organicphase was dried (silicon filter) and concentrated under reducedpressure.

The crude material was purified by preparative HPLC (ACN/H₂O/formic acidsystem). The titled compound was obtained in 18% yield (10 mg). ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm]=1.27 (d, 3H), 2.11 (quin, 2H), 2.99 (t, 2H),3.30 (dt, 1H), 3.56 (dt, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.05 (dd,1H), 4.15 (d, 1H), 4.36 (t, 2H), 4.56-4.64 (m, 1H), 6.82 (s, 1H), 7.36(d, 1H), 7.61 (d, 1H), 7.75 (d, 1H), 8.30-8.41 (m, 2H).

Example 1944-(4-cyclopropyl-1H-1,2,3-triazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a4-(cyclopropylethynyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine

2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yltrifluoromethanesulfonate(150 mg, 284 μmol), copper(I) iodide (5.53 mg, 98% purity, 28.4 μmol)and triethylamine (790 μl, 5.7 mmol) were dissolved in acetonitrile (4.0mL). The reaction mixture was degassed with Argon. Ethynylcyclopropane(74 μl, 98% purity, 850 μmol) and:Bis(triphenylphosphin)palladium(II)chlorid (8.15 mg, 98% purity, 11.4μmol) were added sequentially and the reaction was stirred for 16 h at45° C. The reaction was then filtered and concentrated under reducedpressure. The residue was dissolved in DCM and water and the aqueousphase was extracted 3× with DCM. The combined organic layers were dried(silicone filter) and concentrated under reduced pressure. The crudematerial was purified by flash column chromatography (Hex/EtOAc mixture)and the title compound was obtained in 87% yield (110 mg). 1H-NMR (400MHz, DMSO-d6): δ [ppm]=0.90-0.98 (m, 2H), 1.01-1.08 (m, 2H), 1.15-1.22(m, 3H), 1.39-1.50 (m, 2H), 1.52-1.65 (m, 1H), 1.72-1.81 (m, 1H),1.94-2.01 (m, 2H), 2.31-2.39 (m, 1H), 3.11-3.30 (m, 2H), 3.40-3.51 (m,1H), 3.56-3.64 (m, 1H), 3.65-3.77 (m, 2H), 3.90-3.98 (m, 1H), 4.07-4.16(m, 1H), 4.42-4.53 (m, 1H), 6.07 (ddd, 1H), 6.92 (dd, 1H), 7.53 (d, 1H),7.62 (d, 1H), 7.80 (d, 1H), 8.44 (d, 1H).

Step b4-(4-cyclopropyl-1H-1,2,3-triazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

4-(cyclopropylethynyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine (70.0 mg, 158μmol) was solubilised in tert. Butanol (1.8 mL) and water (1.8 mL).Sodium azide (10.3 mg, 158 μmol) was added and the mixture was stirredfor 5 min. at rt. Copper(II) sulphate hydrate (19.7 mg, 78.9 μmol) and(+)-sodium L-ascorbate (15.6 mg, 78.9 μmol) were added and the mixturewas stirred for 16 h at 100° C.

The reaction was then cooled to rt, diluted with DCM and washed withH2O. The organic phase was dried and concentrated under reducedpressure. The crude material was purified by preparative HPLC(H₂O/CAN/formic acid mixture). The title compound was obtained in 1%yield (1 mg).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.82-0.89 (m, 2H), 0.94-1.00 (m, 2H),1.22-1.29 (m, 1H), 1.31 (d, 3H), 1.89-1.99 (m, 1H), 3.52-3.65 (m, 2H),3.71-3.77 (m, 1H), 3.81-3.86 (m, 1H), 4.07 (dd, 1H), 4.17-4.24 (m, 1H),4.56-4.64 (m, 1H), 7.42 (s, 1H), 7.61 (s, 1H), 7.65 (s, 1H), 7.77 (d,1H), 8.37 (d, 1H), 13.44 (br. s., 1H).

The following compounds of Table 1 were prepared according to Scheme 3and in analogy to example 54.

TABLE 1 NMR Example Structure Name 195

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.12 (t, 3H), 2.86-2.97 (m, 1H),3.23-3.29 (m, 1H), 3.81 (s, 8H), 7.41 (s, 1H), 7.61-7.68 (m, 2H), 7.74(s, 1H), 8.41 (d, 1H), 13.43 (s, 1H).4-ethylsulfinyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 196

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 0.94 (d, 3H), 1.40 (d, 3H),3.18-3.27 (m, 1H), 3.81 (d, 8H), 7.41 (s, 1H), 7.63-7.71 (m, 3H), 8.41(d, 1H), 13.45 (s, 1H).2-(morpholin-4-yl)-4-[propan-2-ylsulfinyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 197

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 3H), 2.25-2.35 (m, 2H),3.07 (s, 3H), 3.28-3.34 (m, 1H), 3.37-3.45 (m, 2H), 3.56 (td, 1H), 3.71(dd, 1H), 3.83 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H), 4.40 (t, 2H),4.56-4.65 (m, 1H), 6.83 (s, 1H), 7.37 (s, 1H), 7.61 (s, 1H), 7.82 (d,1H), 8.34 (d, 1H), 13.36 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-[3-(methylsulfonyl)propoxy]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 198

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.83 (s, 8H), 7.35 (br. s., 1H),7.54 (t, 3H), 7.62 (br. s., 1H), 7.71 (d, 1H), 7.89-7.95 (m, 2H), 8.07(s, 1H), 8.30 (d, 1H), 13.38 (br. s, 1H).2-(morpholin-4-yl)-4-(phenylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 199

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.25 (d, 6H), 3.69 (spt, 1H), 3.80(br. s., 8H), 7.37 (br. s, 1H), 7.64 (br. s, 1H), 7.90 (s, 1H), 8.15 (d,1H), 8.48 (d, 1H), 13.46 (br. s, 1H).2-(morpholin-4-yl)-4-(propan-2-ylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 200

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.19 (t, 3H), 3.56 (q, 2H), 3.80(s, 8H), 7.37 (br. s, 1H), 7.64 (br. s, 1H), 7.91 (br. s, 1H), 8.14 (d,1H), 8.49 (d, 1H), 13.44 (br. s, 1H).4-(ethylsulfonyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 201

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.83 (s, 8H), 7.30 (br. s, 1H),7.60-7.69 (m, 3H), 7.72-7.77 (m, 1H), 7.99 (d, 1H), 8.12-8.17 (m, 2H),8.21 (s, 1H), 8.37 (d, 1H), 13.40 (br. s, 1H).2-(morpholin-4-yl)-4-(phenylsulfinyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 202

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.93 (s, 3H), 3.80 (s, 8H), 7.39(d, 1H), 7.61 (d, 1H), 7.65 (d, 1H), 7.82 (s, 1H), 8.41 (d, 1H), 13.42(br. s, 1H). 4-(methylsulfinyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 203

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.20-1.32 (m, 3H), 1.79-1.88 (m,1H), 2.55-2.65 (m, 1H), 2.83-2.97 (m, 1H), 2.97-3.10 (m, 2H), 3.17-3.30(m, 1H), 3.29-3.38 (m, 2H), 3.44-3.62 (m, 2H), 3.64-3.75 (m, 2H),3.77-3.85 (m, 1H), 3.99-4.08 (m, 1H), 4.14-4.24 (m, 1H), 4.56-4.70 (m,1H), 7.29-7.41 (m, 2H), 7.58-7.88 (m, 2H), 8.31-8.41 (m, 1H), 13.37 (br.s, 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-oxidotetrahydro-2H-thiopyran-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 204

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.20-1.31 (m, 3H), 2.11-2.21 (m,1H), 2.25-2.40 (m, 1H), 2.96-3.04 (m, 1H), 3.14-3.24 (m, 1H), 3.26-3.37(m, 2H), 3.43-3.60 (m, 3H), 3.65-3.74 (m, 1H), 3.77-3.85 (m, 1H),3.96-4.08 (m, 2H), 4.14-4.26 (m, 1H), 4.56-4.71 (m, 1H), 5.79 (t, 1H),7.31-7.42 (m, 2H), 7.58-7.91 (m, 2H), 8.38 (dd, 1H), 13.32-13.43 (m,1H). 4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine

The following compounds of Table 2 were prepared according to Scheme 4and in analogy to examples 63, 70, 85 and 107.

TABLE 2 NMR Example Structure Name 205

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.38 (dd, 1H), 3.59(dt, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.06 (dd, 1H), 4.21 (d, 1H),4.62-4.71 (m, 1H), 7.00 (br. s, 1H), 7.39 (d, 1H), 7.63 (s, 2H), 7.99(br. s, 1H), 8.38 (d, 1H), 8.49-8.57 (m, 1H), 12.95-13.63 (m, 2H).2-[(3R)-3-methylmorpholin-4-yl]-4,8-di(1H-pyrazol-5-yl)-1,7-naphthyridine 206

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.97 (s, 6H), 3.70 (t, 4H), 3.78(t, 4H), 6.68 (s, 1H), 7.33 (d, 1H), 7.68 (d, 1H), 8.18 (s, 1H), 8.29(d, 1H), 13.07-13.60 (m, 1H).N,N-dimethyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 207

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.50-3.59 (m, 4H), 3.69-3.77 (m,4H), 7.00 (s, 1H), 7.36 (d, 1H), 7.46-7.59 (m, 5H), 7.63 (d, 1H), 7.76(d, 1H), 8.38 (d, 1H). 2-(morpholin-4-yl)-4-(phenylsulfanyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 208

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 6H), 3.59-3.67 (m, 4H),3.73-3.82 (m, 4H), 3.90-4.01 (m, 1H), 6.24 (s, 1H), 6.69 (d, 1H), 7.30(s, 1H), 7.58 (s, 1H), 7.98 (d, 1H), 8.25 (d, 1H), 13.38 (br. s., 1H).2-(morpholin-4-yl)-N-(propan-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 209

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.38 (t, 3H), 3.27 (q, 2H),3.74-3.8 (m, 8H), 7.21 (s, 1H), 7.37 (br. s., 1H), 7.61 (s, 1H), 7.67(d, 1H), 8.36 (d, 1H), 13.37 (br. s., 1H).4-(ethylsulfanyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 210

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.40 (d, 6H), 3.74-3.80 (m, 8H),4.02 (spt, 1H), 7.32 (s, 1H), 7.36 (br. s., 1H), 7.62 (br. s, 1H), 7.70(d, 1H), 8.36 (d, 1H), 13.36 (br. s., 1H).2-(morpholin-4-yl)-4-(propan-2-ylsulfanyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 211

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.73-3.86 (m, 8H), 6.29-6.36 (m,1H), 6.68-6.74 (m, 1H), 7.11-7.17 (m, 1H), 7.37 (d, 1H), 7.45 (s, 1H),7.63 (d, 1H), 8.01 (d, 1H), 8.38 (d, 1H), 11.66 (br. s, 1H), 13.36 (br.s, 1H). 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1H-pyrrol-2-yl)-1,7-naphthyridine 212

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.71-3.87 (m, 8H), 6.53-6.58 (m,1H), 6.97-7.01 (m, 1H), 7.33-7.43 (m, 3H), 7.62 (br. s, 1H), 7.97 (d,1H), 8.35 (d, 1H), 11.37 (br. s, 1H), 13.37 (br. s, 1H).2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1H-pyrrol-3-yl)-1,7-naphthyridine 213

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.49 (t, 4H), 3.71 (t, 4H), 3.83(s, 3H), 6.71 (s, 1H), 7.10-7.16 (m, 2H), 7.36 (br. s, 1H), 7.56-7.65(m, 3H), 7.79 (d, 1H), 8.40 (d, 1H), 13.39 (br. s, 1H).4-[(4-methoxyphenyl)sulfanyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 214

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.35 (s, 3H), 3.79 (d, 8H), 6.74(s, 1H), 7.38 (br. s., 1H), 7.63 (d, 2H), 8.38 (d, 1H), 8.57 (d, 1H),13.06 (br. s., 1H), 13.37 (br. s, 1H).4-(5-methyl-1H-pyrazol-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 215

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.25 (q, 2H), 2.55 (d, 2H), 3.77(dd, 8H), 3.92 (t, 2H), 7.38 (s, 1H), 7.48 (d, 1H), 7.55 (s, 1H), 7.62(s, 1H), 8.33 (d, 1H), 13.39 (s, 1H).1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyrrolidin-2-one 216

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.54-2.58 (m, 2H), 3.57 (t, 2H),3.71-3.86 (m, 8H), 4.00 (t, 2H), 7.37 (d, 1H), 7.54 (s, 1H), 7.63 (d,1H), 7.94 (d, 1H), 8.38 (d, 1H), 13.34 (br. s, 1H).4-(1,1-dioxido-1,2-thiazolidin-2-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 217

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.86-2.05 (m, 4H), 2.36-2.65 (m,2H), 3.45-3.54 (m, 1H), 3.71-3.84 (m, 9H), 7.36-7.43 (m, 2H), 7.59-7.64(m, 2H), 8.34 (d, 1H), 13.34-13.42 (m, 1H).1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]piperidin-2-one 218

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (t, 3H), 2.25 (d, 3H),3.34-3.40 (m, 1H), 3.52-3.63 (m, 1H), 3.67-3.76 (m, 1H), 3.78-3.85 (m,1H), 4.00-4.09 (m, 1H), 4.17-4.27 (m, 1H), 4.57-4.67 (m, 1H), 6.93-6.99(m, 1H), 7.38-7.46 (m, 2H), 7.49 (d, 1H), 7.64 (br. s, 1H), 7.72 (dd,1H), 8.29 (d, 1H), 8.64 (dd, 1H), 13.42 (br. s, 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methylpyridin-3-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 219

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.13 (dd, 6H), 1.26-1.34 (m, 3H),3.33-3.39 (m, 1H), 3.57 (dt, 1H), 3.71 (dd, 1H), 3.82 (br. d, 1H), 4.04(dd, 1H), 4.22 (d, 1H), 4.57-4.65 (m, 1H), 5.34 (spt, 1H), 7.12 (d, 1H),7.17 (dd, 1H), 7.41 (br. s, 1H), 7.45 (br. s, 1H), 7.64 (br. s, 1H),7.81 (dd, 1H), 8.28 (s, 1H), 8.34 (dd, 1H), 13.38 (br. s, 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 220

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 3.34 (dt, 1H), 3.56(dt, 1H), 3.67-3.74 (m, 1H), 3.80 (s, 4H), 4.03 (d, 1H), 4.16-4.23 (m,1H), 4.58-4.66 (m, 1H), 7.06 (d, 1H), 7.22 (dd, 1H), 7.44 (d, 2H), 7.63(br. s, 1H), 7.82 (dd, 1H), 8.28 (d, 1H), 8.37 (dd, 1H), 13.39 (s, 1H).4-(2-methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 221

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.79 (s, 8H), 7.34-7.45 (m, 2H),7.52-7.68 (m, 4H), 8.34 (d, 1H), 8.79 (dd, 2H), 13.42 (s, 1H).2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(pyridin-4-yl)-1,7-naphthyridine 222

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.13 (d, 3H), 3.13-3.25 (m, 1H),3.43-3.53 (m, 1H), 3.57-3.65 (m, 1H), 3.71-3.78 (m, 1H), 3.78-3.86 (m,4H), 3.95-4.01 (m, 1H), 4.08-4.17 (m, 1H), 6.63 (s, 1H), 7.09-7.16 (m,2H), 7.36 (s, 1H), 7.56-7.63 (m, 3H), 7.78 (d, 1H), 8.39 (d, 1H), 13.38(br. s, 1H). 4-[(4-methoxyphenyl)sulfanyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 223

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 3.33-3.40 (m, 1H),3.41-3.49 (m, 4H), 3.52-3.61 (m, 1H), 3.67-3.78 (m, 5H), 3.79-3.85 (m,1H), 3.99-4.08 (m, 1H), 4.16-4.25 (m, 1H), 4.57-4.68 (m, 1H), 7.04 (t,1H), 7.21 (dd, 1H), 7.42 (br. s, 1H), 7.52-7.68 (m, 2H), 8.20 (d, 1H),8.33 (d, 1H), 13.40 (br. s, 1H).4-[3-fluoro-2-(morpholin-4-yl)pyridin-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5- yl)-1,7-naphthyridine 224

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.12 (s, 3H), 3.79 (s, 8H), 7.01(d, 1H), 7.33 (s, 1H), 7.42 (d, 1H), 7.55 (s, 1H), 7.65 (d, 1H), 8.16(s, 1H), 8.30 (d, 1H), 13.39 (br. s, 1H).4-(6-fluoro-5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 225

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.77 (d, 8H), 4.20 (br. s., 2H),4.61 (br. s., 2H), 7.31-7.42 (m, 1H), 7.64 (br. s., 3H), 8.36 (br. s.,1H), 13.30-13.48 (m, 1H) 3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]-1,3-oxazinan-2-one 226

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.14-2.32 (m, 2H), 3.72-3.83 (m,9H), 4.41-4.60 (m, 2H), 7.37 (s, 1H), 7.54 (d, 1H), 7.62-7.66 (m, 1H),7.73 (s, 1H), 8.37 (d, 1H), 13.27-13.54 (m, 1H).3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]-1,3-oxazolidin-2-one 227

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 3.34-3.39 (m, 1H),3.51-3.61 (m, 1H), 3.67-3.74 (m, 1H), 3.78-3.86 (m, 4H), 3.99-4.07 (m,1H), 4.16-4.24 (m, 1H), 4.57-4.66 (m, 1H), 7.04 (d, 1H), 7.38-7.48 (m,3H), 7.64 (br. s, 1H), 8.27 (d, 1H), 8.41 (d, 1H), 8.60 (s, 1H), 13.40(br. s, 1H). 4-(3-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 228

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 3.30-3.41 (m, 1H),3.52-3.61 (m, 1H), 3.68-3.74 (m, 1H), 3.80-3.85 (m, 1H), 4.01-4.08 (m,1H), 4.16-4.24 (m, 1H), 4.57-4.66 (m, 1H), 7.25 (dd, 1H), 7.39-7.48 (m,2H), 7.62-7.67 (m, 2H), 8.32 (d, 1H), 8.38 (q, 1H).4-(2,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 229

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.31 (d, 3H), 3.37-3.41 (m, 1H),3.52-3.62 (m, 1H), 3.67-3.75 (m, 1H), 3.79-3.87 (m, 1H), 4.01-4.09 (m,1H), 4.17-4.26 (m, 1H), 4.56-4.67 (m, 1H), 7.25 (dd, 1H), 7.41 (br. s,1H), 7.62-7.70 (m, 2H), 8.33 (d, 1H), 8.40 (dd, 1H), 8.55 (br. s, 1H).4-(5-chloro-2-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 230

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 3.34-3.42 (m, 1H),3.51-3.62 (m, 1H), 3.67-3.76 (m, 1H), 3.81 (s, 1H), 4.00-4.09 (m, 1H),4.17-4.26 (m, 1H), 4.58-4.67 (m, 1H), 7.17 (dd, 1H), 7.43 (s, 1H),7.60-7.72 (m, 3H), 8.33 (d, 1H), 8.66 (dd, 1H), 8.83 (d, 1H), 13.44 (br.s., 1H). 4-(3-fluoropyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 231

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (t, 3H), 2.59 (s, 3H),3.28-3.39 (m, 1H), 3.51-3.62 (m, 1H), 3.67-3.75 (m, 1H), 3.77-3.86 (m,1H), 4.00-4.08 (m, 1H), 4.16-4.25 (m, 1H), 4.55-4.64 (m, 1H), 7.03 (dd,1H), 7.42 (br. s., 1H), 7.48-7.56 (m, 2H), 7.65 (s, 1H), 7.90 (d, 1H),8.30 (d, 1H), 13.42 (br. s, 1H).4-(2-chloro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 232

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 2.37 (s, 3H), 2.54(s, 3H), 3.28-3.40 (m, 1H), 3.50-3.62 (m, 1H), 3.66-3.76 (m, 1H),3.78-3.87 (m, 1H), 4.00-4.09 (m, 1H), 4.18-4.27 (m, 1H), 4.60-4.71 (m,1H), 7.36-7.49 (m, 3H), 7.63 (s, 1H), 7.77 (d, 1H), 8.33 (d, 1H), 8.45(d, 1H), 13.43 (s, 1H). 4-(5,6-dimethylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 233

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 2.57 (d, 3H),3.29-3.40 (m, 1H), 3.50-3.62 (m, 1H), 3.66-3.76 (m, 1H), 3.78-3.87 (m,1H), 4.01-4.09 (m, 1H), 4.19-4.28 (m, 1H), 4.61-4.71 (m, 1H), 7.42 (d,2H), 7.54 (s, 1H), 7.64 (br. s., 1H), 7.97 (dd, 1H), 8.34 (d, 1H), 8.52(s, 1H), 13.43 (br. s, 1H). 4-(5-fluoro-6-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 234

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 2.56 (d, 3H),3.28-3.39 (m, 1H), 3.51-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.78-3.86 (m,1H), 4.00-4.08 (m, 1H), 4.16-4.24 (m, 1H), 4.59-4.69 (m, 1H), 7.18 (t,1H), 7.36-7.45 (m, 2H), 7.60-7.70 (m, 3H), 8.35 (d, 1H), 13.41 (br. s.,1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methylthiophen-3-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 235

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 3.27-3.38 (m, 1H),3.52-3.61 (m, 1H), 3.68-3.75 (m, 1H), 3.78-3.85 (m, 4H), 4.00-4.07 (m,1H), 4.10-4.19 (m, 1H), 4.55-4.63 (m, 1H), 7.27 (d, 1H), 7.36-7.44 (m,2H), 7.50 (d, 1H), 7.63 (d, 1H), 7.79 (d, 1H), 8.34 (d, 1H), 13.32 (br.s, 1H). 4-(3-methoxythiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 236

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.29-3.39 (m, 1H),3.52-3.62 (m, 1H), 3.68-3.74 (m, 1H), 3.78-3.85 (m, 1H), 4.01-4.07 (m,1H), 4.17-4.25 (m, 1H), 4.57-4.66 (m, 1H), 7.22 (d, 1H), 7.27 (d, 1H),7.42 (br. s, 1H), 7.50 (br. s, 1H), 7.61-7.66 (m, 1H), 7.74 (d, 1H),8.34 (d, 1H), 13.42 (br. s, 1H). 4-(2-chlorothiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 237

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.32 (dd, 3H), 3.34-3.42 (m, 1H),3.53-3.63 (m, 1H), 3.68-3.76 (m, 1H), 3.77-3.84 (m, 1H), 4.04 (d, 1H),4.24 (d, 1H), 4.60-4.70 (m, 1H), 6.81-6.87 (m, 1H), 7.37-7.42 (m, 1H),7.46-7.51 (m, 1H), 7.63-7.68 (m, 2H), 7.69-7.80 (m, 2H), 8.19 (d, 1H),8.26-8.33 (m, 1H), 8.57 (d, 1H), 9.52 (s, 1H), 13.44 (br. s, 1H).4-(isoquinolin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 238

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 3.35-3.39 (m, 1H),3.50-3.61 (m, 1H), 3.67-3.75 (m, 1H), 3.77-3.86 (m, 1H), 4.00-4.08 (m,1H), 4.16-4.24 (m, 1H), 4.60-4.68 (m, 1H), 7.36 (d, 1H), 7.40 (s, 1H),7.46 (d, 1H), 7.49 (s, 1H), 7.61-7.65 (m, 1H), 7.79 (d, 1H), 8.38 (d,1H), 13.42 (br. s, 1H). 4-(5-chlorothiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 239

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 2.34 (d, 3H),3.35-3.41 (m, 1H), 3.52-3.62 (m, 1H), 3.69-3.75 (m, 1H), 3.80-3.87 (m,1H), 4.01-4.09 (m, 1H), 4.16-4.24 (m, 1H), 4.60-4.68 (m, 1H), 7.39-7.43(m, 2H), 7.46 (s, 2H), 7.64 (s, 1H), 7.87 (d, 1H), 8.39 (d, 1H), 13.42(br. s, 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylthiophen-2-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 240

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 2.25 (s, 3H), 2.54(s, 3H), 3.24-3.31 (m, 1H), 3.52-3.63 (m, 1H), 3.68-3.74 (m, 1H),3.77-3.84 (m, 1H), 3.99-4.09 (m, 1H), 4.16-4.25 (m, 1H), 4.55-4.67 (m,1H), 6.79-6.84 (m, 1H), 7.28 (d, 1H), 7.36 (s, 1H), 7.42 (s, 1H), 7.63(s, 1H), 8.32 (d, 1H), 13.41 (br. s, 1H).4-(2,5-dimethylthiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 241

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.22-1.36 (m, 3H), 1.86-2.03 (m,2H), 2.11 (t, 2H), 2.63-2.78 (m, 2H), 2.95-3.08 (m, 2H), 3.22-3.32 (m,1H), 3.36-3.44 (m, 1H), 3.57 (td, 1H), 3.71 (dd, 1H), 3.82 (d, 1H),3.99-4.12 (m, 1H), 4.20 (d, 1H), 4.59-4.71 (m, 1H), 7.30 (s, 1H), 7.36(d, 1H), 7.62 (d, 1H), 7.85 (d, 1H), 8.37 (d, 1H), 13.34 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-thiopyran-4-yl)-1,7- naphthyridine 242

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 3H), 2.33 (s, 3H), 2.36(m, 2H), 2.60 (t, 2H), 3.16 (br. s., 2H), 3.25-3.32 (m, 1H), 3.55 (td,1H), 3.66-3.73 (m, 1H), 3.77-3.86 (m, 1H), 4.03 (dd, 1H), 4.14-4.21 (m,1H), 4.57-4.68 (m, 1H), 5.90 (dt, 1H), 7.30 (s, 1H), 7.38 (br. s., 1H),7.62 (d, 2H), 8.34 (d, 1H), 13.38 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-8-(1H-pyrazol-5- yl)-1,7-naphthyridine243

1H-NMR (400 MHz, METHANOL-d4): d [ppm] = 1.38 (d, 3H), 2.49 (s, 3H),2.57-2.63 (m, 2H), 2.83 (t, 2H), 3.20-3.26 (m, 2H), 3.40-3.51 (m, 1H),3.64-3.73 (m, 1H), 3.79-3.92 (m, 2H), 4.06-4.17 (m, 2H), 4.53-4.63 (m,1H), 5.86-5.91 (m, 1H), 7.26 (s, 1H), 7.32 (s, 1H), 7.64-7.68 (m, 1H),7.71 (d, 1H), 8.32 (d, 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-8-(1H-pyrazol-5- yl)-1,7-naphthyridine244

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (dd, 3H), 1.62 (td, 1H),1.71-1.81 (m, 2H), 1.88 (d, 1H), 1.99-2.09 (m, 1H), 2.18 (td, 1H), 2.24(d, 3H), 2.79-2.92 (m, 2H), 3.24-3.31 (m, 1H), 3.41-3.51 (m, 1H), 3.57(td, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H),4.57-4.65 (m, 1H), 7.32-7.38 (m, 2H), 7.62 (d, 1H), 7.79 (d, 1H), 8.38(d, 1H), 13.33 (br. s., 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-methylpiperidin-3-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 245

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.21-1.30 (m, 4H), 2.34-2.40 (m,1H), 2.41-2.48 (m, 1H), 2.97-3.02 (m, 1H), 3.25-3.31 (m, 1H), 3.40-3.46(m, 2H), 3.50-3.60 (m, 1H), 3.66-3.74 (m, 1H), 3.78-3.85 (m, 1H),3.99-4.07 (m, 1H), 4.12-4.21 (m, 1H), 4.56-4.64 (m, 1H), 5.86-5.93 (m,1H), 7.27 (d, 1H), 7.38 (s, 1H), 7.58-7.68 (m, 2H), 8.33 (d, 1H), 13.38(br. s, 1H). 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7- naphthyridine 246

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 1.64-1.93 (m, 2H),2.04-2.19 (m, 2H), 3.19-3.27 (m, 2H), 3.36-3.43 (m, 1H), 3.53-3.64 (m,1H), 3.68-3.77 (m, 1H), 3.78-3.90 (m, 3H), 4.02-4.10 (m, 1H), 4.10-4.18(m, 1H), 4.19-4.29 (m, 1H), 4.56-4.68 (m, 1H), 6.54 (d, 1H), 7.16 (d,1H), 7.45 (br. s., 1H), 7.56 (s, 1H), 7.64-7.68 (m, 1H), 7.74 (d, 1H),8.35 (d, 1H), 13.45 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3- yl]-1,7-naphthyridine247

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (s, 3H), 3.34-3.41 (m, 1H),3.51-3.63 (m, 1H), 3.68-3.75 (m, 1H), 3.80-3.87 (m, 1H), 4.01-4.09 (m,1H), 4.17-4.26 (m, 1H), 4.59-4.67 (m, 1H), 7.21-7.27 (m, 1H), 7.43 (s,1H), 7.60 (dd, 1H), 7.65 (d, 2H), 8.32 (d, 1H), 8.51 (d, 1H), 13.44 (br.s, 1H). 4-(4,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 248

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.30-3.38 (m, 1H)3.52-3.62 (m, 1H), 3.72 (dd, 1H), 3.80-3.87 (m, 1H), 3.97 (s, 3H), 4.06(dd, 1H), 4.21 (d, 1H), 4.65 (d, 1H), 7.40 (s, 1H), 7.45 (s, 1H), 7.63(s, 1H), 7.84 (d, 1H), 7.98 (s, 1H), 8.31-8.40 (m, 2H), 13.41 (br. s.,1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 249

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 2.17 (s, 3H),3.27-3.40 (m, 1H), 3.53-3.63 (m, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 3.89(s, 3H), 4.01-4.09 (m, 1H), 4.19 (d, 1H), 4.60 (d, 1H), 7.34 (s, 1H),7.41 (s, 1H), 7.52 (d, 1H), 7.63 (s, 1H), 8.01 (s, 1H), 8.34 (d, 1H),13.41 (br. s., 1H). 4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 250

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 2.27 (s, 3H),3.29-3.33 (m, 1H), 3.58 (td, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 3.87 (s,3H), 4.05 (dd, 1H), 4.19 (d, 1H), 4.60 (d, 1H), 7.30 (s, 1H), 7.42 (br.s., 1H), 7.49 (d, 1H), 7.64 (br. s., 1H), 7.65 (s, 1H), 8.33 (d, 1H),13.41 (br. s., 1H). 4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 251

1H-NMR (400 MHz, CHLOROFORM-d): d [ppm] = 1.38-1.46 (m, 4H), 1.77-1.87(m, 2H), 1.96-2.06 (m, 2H), 2.94 (t, 2H), 3.27-3.39 (m, 2H), 3.53 (td,1H), 3.72 (td, 1H), 3.82-4.05 (m, 3H), 4.18 (dd, 1H), 4.36-4.47 (m, 1H),7.12 (s, 1H), 7.28 (d, 1H), 7.61 (d, 1H), 7.71 (d, 1H), 8.43-8.49 (m,1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(piperidin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 252

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 3.36-3.44 (m, 1H),3.58 (td, 1H), 3.72 (dd, 1H), 3.82 (d, 1H), 4.05 (dd, 1H), 4.18 (d, 1H),4.56 (d, 1H), 7.27 (d, 1H), 7.41 (s, 1H), 7.44 (s, 1H), 7.64-7.66 (m,1H), 8.33 (s, 2H), 13.41 (br. s., 1H), 14.11 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-1,7- naphthyridine 253

1H-NMR (400 MHz, CHLOROFORM-d): d [ppm] = 1.46 (d, 3H), 1.90-2.03 (m,2H), 2.56-2.72 (m, 4H), 3.57 (td, 1H), 3.74 (td, 1H), 3.86-3.98 (m, 2H),4.04 (dd, 1H), 4.20 (dd, 1H), 4.46 (dd, 1H), 4.91 (dd, 1H), 7.16 (s,1H), 7.32 (d, 1H), 7.73 (d, 1H), 7.74 (d, 1H), 7.80 (s, 1H), 7.85 (s,1H), 8.46 (d, 1H). 4-(1-cyclobutyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 254

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.00-1.08 (m, 2H), 1.14-1.20 (m,2H), 1.28 (d, 3H), 3.34 (s, 1H), 3.51-3.61 (m, 1H), 3.68-3.75 (m, 1H),3.80-3.89 (m, 2H), 4.02-4.08 (m, 1H), 4.16-4.23 (m, 1H), 4.60-4.69 (m,1H), 7.39 (s, 1H), 7.45 (s, 1H), 7.63 (d, 1H), 7.83 (d, 1H), 7.97 (d,1H), 8.36 (d, 1H), 8.41 (s, 1H), 13.38 (br. s, 1H).4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 255

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 1.52 (d, 6H),3.29-3.39 (m, 1H), 3.52-3.62 (m, 1H), 3.68-3.76 (m, 1H), 3.80-3.87 (m,1H), 4.01-4.09 (m, 1H), 4.16-4.24 (m, 1H), 4.57-4.69 (m, 2H), 7.39 (s,1H), 7.45 (s, 1H), 7.62 (s, 1H), 7.85 (d, 1H), 7.98 (s, 1H), 8.34-8.41(m, 2H), 13.38 (br. s, 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 256

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.29-3.40 (m, 1H),3.51-3.61 (m, 1H), 3.68-3.75 (m, 1H), 3.81-3.87 (m, 1H), 4.02-4.08 (m,1H), 4.19-4.26 (m, 1H), 4.62-4.70 (m, 1H), 7.40 (s, 1H), 7.57 (s, 1H),7.64 (s, 1H), 7.74 (d, 1H), 7.88 (t, 1H), 8.33 (s, 1H), 8.38 (d, 1H),8.85 (s, 1H), 13.41 (br. s, 1H).4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 257

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.30 (d, 3H), 1.63 (s, 9H),3.34-3.39 (m, 1H), 3.58 (td, 1H), 3.73 (dd, 1H), 3.85 (d, 1H), 4.07 (dd,1H), 4.21 (d, 1H), 4.67 (d, 1H), 7.40 (br. s., 1H), 7.46 (s, 1H), 7.63(s, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.38 (d, 1H), 8.41 (s, 1H), 13.39(br. s., 1H). 4-(1-tert-butyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 258

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.28 (d, 3H), 2.02 (d, 3H), 2.12(d, 3H), 3.27-3.33 (m, 1H), 3.51-3.65 (m, 1H), 3.69-3.76 (m, 1H), 3.78(s, 3H), 3.79-3.85 (m, 1H), 4.00-4.11 (m, 1H), 4.20 (d, 1H), 4.53-4.67(m, 1H), 7.25 (d, 1H), 7.31 (d, 1H), 7.42 (s, 1H), 7.63 (s, 1H), 8.31(d, 1H), 13.41 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,7- naphthyridine 259

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 3H), 3.28-3.38 (m, 1H),3.58 (td, 1H), 3.72 (dd, 1H), 3.82 (d, 1H), 4.02-4.11 (m, 4H), 4.17 (d,1H), 4.50-4.59 (m, 1H), 7.32 (d, 1H), 7.41 (br. s., 1H), 7.44 (s, 1H),7.63 (br. s., 1H), 8.28 (s, 1H), 8.34 (d, 1H), 13.41 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 260

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.34-3.40 (m, 1H),3.58 (td, 1H), 3.69-3.75 (m, 1H), 3.80-3.87 (m, 3H), 4.06 (dd, 1H), 4.21(d, 1H), 4.27 (t, 2H), 4.65 (d, 1H), 5.00 (br. s., 1H), 7.39 (s, 1H),7.45 (s, 1H), 7.64 (d, 1H), 7.86 (d, 1H), 8.01 (s, 1H), 8.34 (s, 1H),8.37 (d, 1H), 13.37 (br. s., 1H).2-(4-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1H-pyrazol-1- ypethanol 261

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 1.48 (t, 3H),3.33-3.40 (m, 1H), 3.53-3.62 (m, 1H), 3.69-3.76 (m, 1H), 3.80-3.88 (m,1H), 4.02-4.10 (m, 1H), 4.17-4.23 (m, 1H), 4.26 (q, 2H), 4.61-4.70 (m,1H), 7.40 (s, 1H), 7.46 (s, 1H), 7.63 (s, 1H), 7.85 (d, 1H), 7.99 (s,1H), 8.35-8.40 (m, 2H), 13.39 (br. s, 1H).4-(1-ethyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 262

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 3H), 3.25-3.32 (m, 1H),3.52-3.61 (m, 1H), 3.68-3.77 (m, 4H), 3.81 (s, 1H), 4.01-4.08 (m, 1H),4.14-4.21 (m, 1H), 4.57-4.66 (m, 1H), 6.51 (dd, 1H), 6.94 (t, 1H), 7.31(s, 1H), 7.34 (t, 1H), 7.38 (d, 1H), 7.62 (d, 1H), 7.97 (d, 1H), 8.34(d, 1H), 13.12 (br. s, 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrrol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 263

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 1.52 (d, 6H),3.27-3.42 (m, 1H), 3.57 (td, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.06 (dd,1H), 4.21 (d, 1H), 4.56-4.72 (m, 2H), 7.40 (s, 1H), 7.46 (s, 1H), 7.64(d, 1H), 7.86 (d, 1H), 7.99 (s, 1H), 8.35-8.42 (m, 2H), 13.40 (br. s.,1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(propan-2-yl)-1H-pyrazol-3-yl]-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 264

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.27 (d, 3H), 2.18 (s, 3H), 2.26(s, 3H), 3.26-3.32 (m, 1H), 3.49 (s, 3H), 3.51-3.62 (m, 1H), 3.72 (dd,1H), 3.82 (d, 1H), 4.05 (dd, 1H), 4.16 (d, 1H), 4.51-4.60 (m, 1H), 6.00(d, 1H), 7.16 (s, 1H), 7.39 (s, 1H), 7.60-7.66 (m, 2H), 8.30 (d, 1H),13.38 (br. s., 1H). 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2,5-trimethyl-1H-pyrrol-3-yl)-1,7- naphthyridine 265

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.32 (d, 3H), 3.36-3.43 (m, 1H),3.59 (td, 1H), 3.74 (dd, 1H), 3.86 (d, 1H), 4.08 (dd, 1H), 4.24 (d, 1H),4.69 (d, 1H), 7.35-7.45 (m, 2H), 7.54-7.62 (m, 3H), 7.65 (s, 1H), 7.94(d, 1H), 7.99 (dd, 2H), 8.32 (s, 1H), 8.40 (d, 1H), 9.10 (s, 1H), 13.43(br. s., 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-phenyl-1H-pyrazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 266

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 2.26 (br. s., 3H),3.58 (td, 1H), 3.28-3.39 (m, 1H), 3.72 (dd, 1H), 3.83 (d, 1H), 4.06 (dd,1H), 4.19 (d, 1H), 4.61 (d, 1H), 7.34 (s, 1H), 7.42 (br. s., 1H), 7.51(d, 1H), 7.63 (s, 1H), 7.69-7.87 (m, 1H), 8.34 (d, 1H), 13.02 (br. s.,1H), 13.41 (br. s., 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1H-pyrazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 267

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.23 (d, 3H), 3.24 (td, 1H), 3.55(td, 1H), 3.70 (dd, 1H), 3.81 (d, 1H), 3.92 (d, 1H), 4.03 (dd, 1H), 4.34(dd, 1H), 6.36 (s, 1H), 6.73 (s, 2H), 7.30 (s, 1H), 7.58 (s, 1H), 7.83(d, 1H), 8.24 (d, 1H), 13.40 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 268

1H-NMR (400 MHz, CHLOROFORM-d): d [ppm] = 1.01 (d, 6H), 1.46 (d, 3H),2.33 (dt, 1H), 3.51-3.61 (m, 1H), 3.72 (td, 1H), 3.84-3.90 (m, 1H),3.90-3.97 (m, 1H), 3.99-4.08 (m, 3H), 4.18 (dd, 1H), 4.42-4.50 (m, 1H),7.15 (s, 1H), 7.31 (d, 1H), 7.69 (d, 1H), 7.71-7.75 (m, 2H), 7.81 (s,1H), 8.44 (d, 1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-8-(1H-pyrazol-5- yl)-1,7-naphthyridine269

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.29 (d, 3H), 3.30-3.38 (m, 1H),3.53-3.62 (m, 1H), 3.73 (dd, 1H), 3.84 (d, 1H), 4.03-4.09 (m, 1H), 4.21(d, 1H), 4.66 (d, 1H), 7.41 (s, 1H), 7.47 (s, 1H), 7.63 (s, 1H), 7.84(d, 1H), 8.03 (s, 1H), 8.37 (d, 2H), 13.37 (br. s., 1H), 13.41 (br. s.,1H). 2-[(3R)-3-methylmorpholin-4-yl]-4-(1H-pyrazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 270

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.31 (d, 3H), 3.40-3.44 (m, 1H),3.55-3.64 (m, 1H), 3.71-3.77 (m, 1H), 3.82-3.87 (m, 1H), 4.03-4.11 (m,1H), 4.19-4.25 (m, 1H), 4.62-4.69 (m, 1H), 7.40 (br. s., 1H), 7.64 (br.s., 1H), 7.68 (d, 1H), 8.00 (s, 1H), 8.47 (d, 1H), 8.49 (d, 1H), 8.82(d, 1H), 13.44 (br. s., 1H).2-[(3R)-3-methylmorpholin-4-yl]-4-(1,3-oxazol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 271

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.16 (s, 3H), 3.72-3.84 (m, 8H),3.88 (s, 3H), 7.35-7.43 (m, 2H), 7.50 (d, 1H), 7.63 (br. s., 1H), 8.00(s, 1H), 8.34 (d, 1H), 13.40 (br. s., 1H).4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 272

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.25 (s, 3H), 3.71-3.82 (m, 8H),3.86 (s, 3H), 7.35 (s, 1H), 7.40 (br. s., 1H), 7.48 (d, 1H), 7.64 (s,2H), 8.33 (d, 1H), 13.40 (br. s., 1H).4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 273

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 2.00 (s, 3H), 2.10 (s, 3H),3.71-3.86 (m, 11H), 7.24 (d, 1H), 7.36 (s, 1H), 7.41 (br. s., 1H), 7.64(s, 1H), 8.32 (d, 1H). 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,7-naphthyridine

The following compounds of Table 3 were prepared according to Scheme 6and in analogy to example 126.

TABLE 3 NMR Example Structure Name 274

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.25 (d, 3H), 3.23-3.29 (m, 1H),3.30 (s, 3H), 3.35-3.41 (m, 1H), 3.43 (d, 2H), 3.56 (td, 1H), 3.67-3.74(m, 1H), 3.78-3.92 (m, 5H), 3.95-4.08 (m, 2H), 4.34-4.47 (m, 1H), 6.81(d, 1H), 7.35 (s, 1H), 7.60 (s, 1H), 7.87 (d, 1H), 8.29 (d, 1H), 13.36(br. s., 1H). 4-{[(2-methoxyethyl)(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 275

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 0.94 (dd, 3H), 1.31 (dd, 3H), 1.48(q, 3H), 3.03-3.15 (m, 1H), 3.41-3.52 (m, 1H), 3.53-3.92 (m, 4H),3.93-4.10 (m, 2H), 6.45 (d, 1H), 7.26-7.32 (m, 1H), 7.58 (s, 1H), 7.79(t, 2H), 7.84-7.91 (m, 2H), 8.06 (q, 1H), 8.36 (d, 1H), 13.29 (br. s,1H). 4-{[(4-bromophenyl)(oxido)propan-2-yl-λ⁶-sulfanylidenelamino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 276

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 0.80-1.18 (m, 3H), 3.61-3.66 (m,1H), 3.69 (s, 4H), 3.72-3.89 (m, 2H), 3.93-4.04 (m, 2H), 4.05-4.13 (m,1H), 6.42 (d, 1H), 6.83-6.94 (m, 1H), 6.96-7.05 (m, 1H), 7.24-7.30 (m,1H), 7.40-7.50 (m, 1H), 7.56 (s, 1H), 7.91-8.00 (m, 2H), 8.26-8.30 (m,1H), 11.28 (br. s, 1H). 2-(methyl-N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4- yl}sulfonimidoyl)phenol 277

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 0.81 (d, 1H), 1.17 (d, 2H),3.06-3.18 (m, 1H), 3.42-3.54 (m, 1H), 3.55-3.67 (m, 1H), 3.68-3.79 (m,4H), 3.81-3.92 (m, 1H), 3.93-4.03 (m, 1H), 4.09-4.18 (m, 1H), 6.49 (d,1H), 7.29 (d, 1H), 7.57 (s, 1H), 7.84-7.90 (m, 2H), 7.91-7.99 (m, 2H),8.03 (dd, 1H), 8.34 (dd, 1H), 13.31 (br. s, 1H).4-{[(4-bromophenyl)(methyl)oxido-λ⁶- sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 278

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.22-1.29 (m, 3H), 1.55 (d, 9H),3.25-3.30 (m, 1H), 3.32 (s, 3H), 3.52-3.62 (m, 1H), 3.72 (dd, 1H),3.80-3.86 (m, 1H), 3.94-4.09 (m, 2H), 4.33-4.48 (m, 1H), 6.83-6.93 (m,1H), 7.29-7.37 (m, 1H), 7.60 (d, 1H), 7.84 (d, 1H), 8.29 (d, 1H),13.15-13.44 (m, 1H). 4-{[tert-butyl(methyl)oxido-λ⁶-sulfanylidene]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl]- 1,7-naphthyridine 279

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 3.59-3.67 (m, 6H), 3.77-3.86 (m,6H), 3.96 (t, 2H), 4.13-4.20 (m, 2H), 6.84 (s, 1H), 7.35 (d, 1H), 7.61(d, 1H), 7.98 (d, 1H), 8.17 (s, 1H), 8.33 (d, 1H). formicacid-N42-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]-1,4λ⁴- oxathian-4-imine 4-oxide(1:1) 280

1H-NMR (400 MHz, DMSO-d6): d [ppm] = 1.55-1.75 (m, 2H), 1.85-2.07 (m,4H), 3.42-3.53 (m, 2H), 3.62 (t, 4H), 3.71 (d, 2H), 3.76-3.84 (m, 4H),6.82 (s, 1H), 7.36 (s, 1H), 7.60 (s, 1H), 7.95 (d, 1H), 8.32 (d, 1H),13.37 (s, 1H). N-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]hexahydro-1λ⁴-thiopyran-1- imine 1-oxide

Example 2813-methyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-olStep a2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine-4-carboxylicacid

Methyl2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2E)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine-4-carboxylate(1.10 g, 2.51 mmol) was solubilized in THF (11 mL) and methanol (5 mL9).NaOH solution (2.8 ml, 1.0 M, 2.8 mmol) was added and the mixture wasstirred for 10 min at rt. The solvent was removed under reduced pressureand the aqueous phase was acidified to pH 5 using 1M HCl. The aqueoussolution was lyophilised and the title compound was obtained withoutfurther purification in 99% yield (1.10 g).

1H-NMR (400 MHz, DMSO-d6): d [ppm]=1.18 (dd, 3H), 1.37-1.49 (m, 2H),1.51-1.64 (m, 1H), 1.88-2.03 (m, 2H), 2.29-2.40 (m, 1H), 3.09-3.19 (m,1H), 3.19-3.28 (m, 1H), 3.41-3.51 (m, 1H), 3.58-3.65 (m, 1H), 3.66-3.78(m, 2H), 3.89-4.00 (m, 1H), 4.06 (t, 1H), 4.36-4.51 (m, 1H), 5.92-6.08(m, 1H), 6.84 (dd, 1H), 7.48 (d, 1H), 7.60 (s, 1H), 8.32 (d, 1H),8.46-8.53 (m, 1H).

Step bN-methoxy-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine-4-carboxamide

N-methoxymethanamine hydrochloride (1:1) (861 mg, 8.83 mmol) wassolubilized in DMF (20 mL). N,N-Diisopropylethylamin (3.1 ml, 18 mmol)and HATU (2.52 g, 6.62 mmol) were added and the mixture stirred for 10min at rt.2-[(3R)-3-Methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine-4-carboxylicacid (1.10 g, 85% purity, 2.21 mmol) was then added and the mixturestirred 16 h at rt. N,N-Diisopropylethylamin (3.1 ml, 18 mmol) and HATU(2.52 g, 6.62 mmol) were added again and the reaction stirred for 16 hat rt. Water was added and the mixture was stirred for 10 min. Theaqueous phase was extracted with EtOAc and the combined organic layerswere washed with half sat. NaCl-solution. The organic layer was driedover a silicone filter and concentrated under reduced pressure. Thecrude material was purified by flash column chromatograpy (fromHx/EtOAc: 0-100% to 100% EtOAc to EtOAc/EtOH: 0-20%) and the titlecompound was obtained in quantitative yield.

1H-NMR (400 MHz, DMSO-d6): d [ppm]=1.19-1.25 (m, 3H), 1.41-1.54 (m, 2H),1.54-1.66 (m, 1H), 1.92-1.99 (m, 2H), 2.69 (s, 2H), 3.15-3.32 (m, 2H),3.42 (br. s., 3H), 3.50 (br. s., 3H), 3.60-3.72 (m, 2H), 3.72-3.80 (m,1H), 3.93-4.01 (m, 1H), 4.12-4.22 (m, 1H), 4.46-4.57 (m, 1H), 6.04-6.17(m, 1H), 6.97 (dd, 1H), 7.44 (d, 1H), 7.58-7.67 (m, 2H), 8.41 (d, 1H).

Step c1-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)ethanone

N-methoxy-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridine-4-carboxamide(710 mg, 1.52 mmol) was solubilized in THF and cooled to 0° C.Methylmagnesium bromide (1.5 ml, 3.0 M, 4.6 mmol) was added dropwise andthe reaction was stirred at 0° C. for 30 min. and 1.5 h at rt.Methylmagnesium bromide (1.5 ml, 3.0 M, 4.6 mmol) was added again andthe reaction was stirred for 16 h. The reaction was quenched with sat.NH₄Cl and extracted with DCM. The organic phase was filtered andconcentrated under reduced pressure. The title compound was used withoutfurther purification.

1H-NMR (400 MHz, DMSO-d6): d [ppm]=1.23 (dd, 3H), 1.40-1.48 (m, 2H),1.53-1.64 (m, 1H), 1.95-2.00 (m, 1H), 2.32-2.40 (m, 1H), 2.69 (s, 3H),2.78 (s, 2H), 3.19-3.30 (m, 2H), 3.64-3.73 (m, 2H), 3.75-3.81 (m, 1H),3.95-4.02 (m, 1H), 4.14-4.21 (m, 1H), 4.55-4.63 (m, 1H), 5.97-6.07 (m,1H), 6.88 (dd, 1H), 7.63 (t, 1H), 7.85 (d, 1H), 7.95 (d, 1H), 8.42 (d,1H).

Step d3-methyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol

1-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)ethanone(33.0 mg, 78.3 μmol) was solubilized in THF (2.0 mL) and the mixture wascooled to 0° C. Chloro(propan-2-yl)magnesium (120 μl, 2.0 M, 230 μmol)was added dropwise. The mixture was stirred at 0° C. 0.5 h and 1.5 h atrt. The reaction mixture was quenched with water and of 3M aq. HCl (0.5mL) was added. The mixture was stirred for 16 h at rt. The reaction wasquenched with NaHCO₃ and extracted with DCM. The organic phase was driedover a silicone filter and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC (ACN/H₂O/NH₄OH mixture)and the title compound was obtained in 27% yield (9 mg).

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.75-0.89 (m, 6H), 1.26 (d, 3H), 1.63(d, 3H), 3.59 (t, 1H), 3.71-3.78 (m, 1H), 3.80-3.88 (m, 1H), 4.03-4.16(m, 2H), 4.50-4.60 (m, 1H), 5.39 (d, 1H), 7.35 (s, 1H), 7.43 (s, 1H),7.60 (s, 1H), 8.27-8.32 (m, 2H), 13.34 (br. s., 1H).

Example 2821-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}-1-(tetrahydro-2H-pyran-4-yl)ethanol

1-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)ethanone(33.0 mg, 78.3 μmol) was solubilized in THF (2.0 mL) and the mixture wascooled to 0° C. Chloro(tetrahydro-2H-pyran-4-yl)magnesium (1.4 ml, 0.50M, 710 μmol) was added dropwise. The mixture was stirred at 0° C. 0.5 hand 1.5 h at rt. The mixture was cooled to 0° C. andchloro(tetrahydro-2H-pyran-4-yl)magnesium (1.4 ml, 0.50 M, 710 μmol) wasagain added. The reaction was stirred at 0° C. for 30 min and 45 at rt.The reaction mixture was quenched with water and of 3M aq. HCl (0.5 mL)was added. The mixture was stirred for 72 h at rt. The reaction wasquenched with NaHCO₃ and extracted with DCM. The organic phase was driedover a silicone filter and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC (ACN/H₂O/NH₄OH mixture)and the title compound was obtained in 23% yield (25 mg).

1H-NMR (400 MHz, DMSO-d6): d [ppm]=1.25 (d, 4H), 1.34-1.45 (m, 2H),1.45-1.56 (m, 1H), 1.64-1.68 (m, 3H), 2.24-2.35 (m, 1H), 3.06-3.24 (m,2H), 3.26-3.32 (m, 1H), 3.57 (t, 1H), 3.69-3.90 (m, 5H), 4.02-4.14 (m,2H), 4.48-4.58 (m, 1H), 5.48 (d, 1H), 7.33 (br. s., 1H), 7.45 (d, 1H),7.60 (s, 1H), 8.24-8.34 (m, 2H), 13.33 (br. s., 1H).

Example 2833,3-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}butan-2-ol

1-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)ethanone(33.0 mg, 78.3 μmol) was solubilized in THF (2.0 mL) and the mixture wascooled to 0° C. tert-butyl(chloro)magnesium (710 μl, 1.0 M, 710 μmol)was added dropwise. The mixture was stirred at 0° C. 0.5 h and 1.5 h atrt. The reaction mixture was quenched with water and of 3M aq. HCl (0.5mL) was added. The mixture was stirred for 72 h at rt. The reaction wasquenched with NaHCO₃ and extracted with DCM. The organic phase was driedover a silicone filter and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC (ACN/H₂O/NH₄OH mixture)and the title compound was obtained in 24% yield (25 mg).

1H-NMR (400 MHz, DMSO-d6): d [ppm]=0.94 (s, 9H), 1.14-1.30 (m, 3H), 1.70(s, 3H), 3.19-3.31 (m, 1H), 3.58 (t, 1H), 3.67-3.75 (m, 1H), 3.75-3.86(m, 1H), 3.98-4.17 (m, 2H), 4.53 (br. s., 1H), 5.59 (s, 1H), 7.10 (br.s., 1H), 7.31 (br. s., 1H), 7.58 (s, 1H), 8.26 (d, 1H), 8.92 (br. s.,1H), 13.30 (br. s., 1H).

Example 2842-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}hexan-2-ol

1-(2-[(3R)-3-methylmorpholin-4-yl]-8-{1-[(2R)-tetrahydro-2H-pyran-2-yl]-1H-pyrazol-5-yl}-1,7-naphthyridin-4-yl)ethanone(33.0 mg, 78.3 μmol) was solubilized in THF (2.0 mL) and the mixture wascooled to 0° C. Butyl(chloro)magnesium (360 μl, 2.0 M, 710 μmol) wasadded dropwise. The mixture was stirred at 0° C. 0.5 h and 1.5 h at rt.The reaction mixture was quenched with water and of 3M aq. HCl (0.5 mL)was added. The mixture was stirred for 72 h at rt. The reaction wasquenched with NaHCO₃ and extracted with DCM. The organic phase was driedover a silicone filter and concentrated under reduced pressure. Thecrude material was purified by preparative HPLC (ACN/H₂O/NH₄OH mixture)and the title compound was obtained in 7% yield (7 mg).

1H-NMR (400 MHz, DMSO-d6): d [ppm]=0.77 (td, 3H), 0.97-1.08 (m, 1H),1.12-1.22 (m, 3H), 1.27 (d, 4H), 1.68 (d, 3H), 1.87-2.00 (m, 1H),2.02-2.14 (m, 1H), 3.58 (t, 1H), 3.73 (d, 1H), 3.84 (d, 1H), 4.01-4.16(m, 2H), 4.55 (d, 1H), 5.47 (d, 1H), 7.35 (s, 1H), 7.47 (d, 1H), 7.61(s, 1H), 8.22 (dd, 1H), 8.32 (d, 1H), 13.35 (br. s., 1H).

Example 2852-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-3-yl)-1,7-naphthyridine-4-carboxamideStep a2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxamide

2-((R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine-4-carbonitrile(1.5 g, 3.882 mmol) were suspended in 2-methoxyethanol (15 ml). Then KOH(0.653 g, 11.645 mmol) in water (367 μl) were added and the reaction wasstirred at 150° C. for 7 hours and at 130° C. for 14 hours. The solventwas removed by distillation under reduced pressure and the residue wascrystallized from a mixture of isopropanol (5 ml) and diethylether (25ml). The title compound was obtained by filtration as a yellow solid in6% yield (95 mg). LC-MS (method 1): m/z: [M+H]+=423.2, R_(t)=3.01 min.

Step b2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-3-yl)-1,7-naphthyridine-4-carboxamide

To 2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxamide (95mg, 0.22 mmol) was added a drop of water and trifluoroacetic acid (1 ml,13 mmol). After 2 hours LCMS indicated the complete removal of theprotective group. The trifluoroacetic acid was removed under reducedpressure and the residue was adjusted to pH 7 by addition of aq. NaHCO₃solution. The aqueous layer was extracted with a mixture ofdichloromethane/isopropanol (10:1, 5×). The combined organic layers weredried over sodium sulfate and the solvent was evaporated. The residuewas purified in a flashmaster chromatography (25 g of silica gel 60, 30μM) with chloroform/methanol 90:10 as eluent. The title compound wasobtained in 19% yield (14 mg) as a yellow solid. Melting point: 145-147°C. ¹H-NMR (400 MHz, CD₃OD): δ [ppm]=1.40-1.41 (m, 3H), 3.49-3.52 (m,1H), 3.65-3.71 (m, 1H), 3.82-3.91 (m, 2H), 4.10-4.18 (m, 2H), 4.60-4.61(m, 1H), 7.34 (s, 1H), 7.56 (s, 1H), 7.67 (s, 1H), 7.86-7.87 (m, 1H),8.37-8.38 (m, 1H). LC-MS (method 1): m/z: [M+H]+=339.2, R_(t)=2.23 min.

Example 2862-[(3R)-3-methylmorpholin-4-yl]-4-[1-(methylsulfonyl)cyclopropyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridineStep a{2-((R)-3-methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl}methanol

To a solution ofmethyl-2-((R)-3-Methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-carboxylate(190.5 mg, 0.435 mmol) in absolute THF (19 ml) was addeddiisobutylaluminium hydride solution (1M in toluene, 871 μl, 0.871 mmol)under argon at ambient temperature and the reaction was stirred for 1.5hours at 80° C. The reaction mixture was cooled with ice, a saturatedaqueous ammonium chloride solution (20 ml) was added and the aqueouslayer was extracted with ethyl acetate (3×30 ml). The combined organiclayers were dried over sodium sulfate and the solvent was removed underreduced pressure. The residue was purified in a Flashmasterchromatography (silica gel 60, 30 μM) using chloroform/methanol 98:2 aseluent. The title compound was obtained in 66% yield (118 mg). LC-MS(method 1): m/z: [M+H]+=410.3, R_(t)=3.07 min.

Step b{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}methylmethanesulfonate

To a solution of{2-((R)-3-Methylmorpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridine-4-yl}methanol(118 mg, 0.288 mmol) and trimethylamine (52 μl, 0.375 mmol) in absoluteTHF (5 ml) was added dropwise under argon at 0° C. methansulfonylchloride (25 μl, 0.317 mmol) and the reaction was allowed to stir forone hour at 0° C. With intervals of two hours additional methansulfonylchloride (3×25 μl, 0.317 mmol) were added and the reaction was allowedto stir for another 16 hours at ambient temperature. After addition ofanother portion of methansulfonyl chloride (25 μl, 0.317 mmol) thereaction was stirred at 40° C. for two hours. The reaction mixture wasfiltered and the filtrate was evaporated. The title compound wasobtained in quantitative yield (219 mg) and used without furtherpurification in the next step. LC-MS (method 1): m/z: [M+H]+=488.2,Rt=3.32 min.

Step c2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfonyl)methyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

To a solution of{2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}methylmethanesulfonate (219 mg, 0.45 mmol) in absolute DMSO (2 ml) was addedportionwise sodium methylsulfinate (161 mg, 1.572 mmol) and the reactionwas allowed to stir at 120° C. for 20 minutes. The reaction was dilutedwith water (10 ml) and extracted with dichloromethane (3×10 ml). Thecombined organic layers were dried over sodium sulfate and the solventwas removed under reduced pressure. The residue was purified byPuri-Flash chromatography (25 g of silica gel 60, 30 μm) usingdichloromethane/methanol 95:5 as eluent. The title compound was obtainedin 40% yield (84 mg) as a yellow solid. LC-MS (method 1): m/z:[M+H]+=472.3, R_(t)=3.06 min.

Step d2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(methylsulfonyl)cyclopropyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine

To a solution of2-[(3R)-3-methylmorpholin-4-yl]-4-[(methylsulfonyl)methyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(84 mg, 0.178 mmol), 1,2-dibromoethane (15 μl, 0.178 mmol) andtetrabutylammoniumbromide (6 mg, 0.018 mmol) in absolute THF (1.68 ml)was added a NaOH solution (50% in water, 185 μl) and the reaction wasstirred at ambient temperature for one hour. The suspension changed itscolor to dark green/dark brown. Additional 1,2-dibromoethane (15 μl,0.178 mmol), tetrabutylammoniumbromide (6 mg, 0.018 mmol) and NaOHsolution (50% in water, 185 μl) were added and the reaction was stirredat 60° C. for 5 hours. The reaction was diluted with water (10 ml) andextracted with dichloromethane (3×10 ml). The combined organic layerswere dried over sodium sulfate and the solvent was removed under reducedpressure. The residue was purified in a Flashmaster chromatography (25 gof silica gel 60, 30 μm) using dichloromethane/methanol 95:5 as eluent.The title compound was obtained in 28% yield (25 mg) as yellow solid.The product was used in the next step without further purification.LC-MS (method 1): m/z: [M+H]⁺=498.3, R_(t)=3.27 min.

Step e2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(methylsulfonyl)cyclopropyl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine

To a solution of2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(methylsulfonyl)cyclopropyl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridine(25 mg, 0.05 mmol) in methanol (2 ml) was added HCl (2N in water). Thereaction was stirred for 18 hours at 50° C. The LCMS indicated completeremoval of the protective group. Methanol was removed under reducedpressure and the pH value of the residue was adjusted to seven byaddition of aqueous NaHCO₃ solution. The aqueous layer was extractedwith dichloromethane (3×10 ml). The combined organic layers were driedover sodium sulfate and the solvent was removed under reduced pressure.The title compound was obtained in 73% yield (16 mg) as a yellow solid.Melting point: 240-248° C. ¹H-NMR (400 MHz, CDCl₃): δ [ppm]=0.06-0.09(m, 3H), 0.83-089 (m, 1H), 1.22-1.53 (m, 1H), 1.97-2.36 (m, 2H), 2.86(s, 3H), 3.51-3.58 (m, 1H), 3.67-3.75 (m, 1H), 3.83-3.88 (m, 1H),3.91-3.95 (m, 1H), 3.98-4.03 (m, 1H), 4.16-4.20 (m, 1H), 4.39-4.46 (m,1H), 7.32 (s, 1H), 7.45 (s, 1H), 7.71 (s, 1H), 7.82-7.83 (m, 1H),8.48-8.49 (m, 1H). LC-MS (method 1): m/z: [M+H]+=414.2, R_(t)=2.65 min.

Example 2872-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)-1,7-naphthyridine

A mixture of2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(75 mg, 0.1 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (26.4 mg, 147.5μmol) and cesiumcarbonate (41.6 mg, 127.8 μM) in DMF (0.6 ml) was heatedin a microwave reactor at 100° C. for one hour. The reaction mixture wascooled to ambient temperature and conc. HCl (0.13 ml) was added slowly(gas evolution). The reaction was stirred at ambient temperature for 14hours. The solvent was evaporated and the residue was extracted withdichloromethane (10 ml) and water (10 ml). The layers were separated andthe aqueous layer was extracted with dichloromethane (2×10 ml). Thecombined organic layers were dried over sodium sulfate and the solventwas removed under reduced pressure. The title compound was obtainedafter HPLC separation in 3% yield (1 mg). ¹H-NMR (400 MHz, CD₂Cl₂,selected peaks): δ [ppm]=1.86 (m, 2H), 3.52 (m, 2H), 3.64 (m, 1H), 3.77(m, 4H), 3.95 (m, 4H), 4.07 (m, 4H), 6.51 (s, 1H), 7.26 (d, 1H), 7.67(d, 1H), 7.79 (d, 1H), 8.42 (d, 1H).

Example 288N,N-dimethyl-3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]benzamide

To a solution of [3-(dimethylcarbamoyl)phenyl]boronic acid (530 μl, 0.57M, 300 μmol) in 0.52 mL DMF was added2-(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]naphthyridin-4-yl-trifluoromethanesulphonate(1.0 ml, 0.15 M, 150 μmol; Intermediate-3) in 1 mL DMF, aqueous sodiumcarbonate solution (200 μl, 2.3 M, 450 μmol) and1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (400 μl, 0.038M in DMF, 15 μmol). The reaction mixture was shaked at 90° C. for 12 h.

To the crude reaction mixture aqueous hydrochloric acid (240 μl, 1.9 M,470 μmol) was added and the corresponding mixture was shaked over nightat room temperature.

The reaction mixture was purified by preparative HPLC to give 22 mg ofthe product as solid material.

LC-MS Method 4: R_(t)=0.75 min; MS (ESIpos) m/z=429 [M+H]⁺.

The following examples (Table 4) were prepared in analogy to example288:

TABLE 4 Retention LC-MS time m/z Example Structure Name [min] [M + H]⁺289

{4-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}(piperidin-1- yl)methanone 0.88 469 290

N,N-dimethyl-2-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]benzamide 0.74 429 291

N-cyclopropyl-4-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]benzamide 0.76 441 292

4-(4-methylpyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.65 373 293

4-(1H-indol-6-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.86 397 294

4-(1H-indol-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.82 397 295

3-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]benzamide 0.68 401 296

4-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]benzamide 0.66 401 297

N-methyl-3-[2-(morpholin-4- yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]benzamide 0.71 415 298

4-(3-fluorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.92 376 299

4-(5-chlorothiophen-2-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.06 398 300

4-(2-methoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.86 388 301

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-[2-(trifluoromethyl)phenyl]-1,7- naphthyridine 1.00 426 302

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-[4-(trifluoromethyl)phenyl]-1,7- naphthyridine 1.08 426 303

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-[3-(trifluoromethyl)phenyl]-1,7- naphthyridine 1.06 426 304

4-(3-chlorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.01 392 305

N-{3-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]phenyl}acetamide 0.73 415 306

4-(3-methoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.90 388 307

4-(3,5-dimethoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.93 418 308

4-(3-methylphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.96 372 309

4-(4-methoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.88 388 310

4-(furan-2-ylmethyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.78 362 311

2,6-dimethyl-4-[2-(morpholin- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenol 0.83 402 312

4-(2,3-dimethylphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.00 386 313

{3-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}methanol 0.73 388 314

4-(4-fluorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.90 376 315

4-(4-methylphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.96 372 316

4-(4-chlorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.01 392 317

4-(2-fluoro-3-methoxyphenyl)- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.90 406 318

4-(2-methylphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.94 372 319

4-(2,3-dimethoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.87 418 320

N,N-dimethyl-3-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]aniline 0.93 401 321

N,N-dimethyl-2-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]aniline 0.92 401 322

N-{2-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]phenyl}methanesulfonamide 0.75 451 323

N-{4-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]phenyl}methanesulfonamide 0.74 451 324

N,N-dimethyl-4-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]benzamide 0.74 429 325

2-(morpholin-4-yl)-4-[(1E)- prop-1-en-1-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine 0.76 322 326

4-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin- 4-yl]phenol0.72 374 327

4-(2-fluorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.90 376 328

{3-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]phenyl}(piperidin-1- yl)methanone 0.88 469 329

2-(morpholin-4-yl)-4-[4- (propan-2-yl)phenyl]-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.12 400 330

N-cyclopropyl-3-[2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin- 4-yl]benzamide 0.77 441 331

4-(biphenyl-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.14 434 332

4-(2,4-dimethoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.87 418 333

4-(2-chlorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.96 392 334

4-(2,5-dimethylphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.02 386 335

3-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]aniline 0.72 373 336

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-[3-(1H-pyrazol-1-yl)phenyl]-1,7- naphthyridine 0.89 424 337

3-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin- 4-yl]phenol0.75 374 338

4-(2-fluoro-5-methoxyphenyl)- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.93 406 339

4-(5-fluoro-2-methoxyphenyl)- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.90 406 340

4-(2,4-difluorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.94 394 341

4-(2,3-difluorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.95 394 342

4-(2,6-dimethoxyphenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.85 418 343

2-[2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]aniline 0.79 373 344

4-(3,5-dichlorophenyl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.19 426 345

4-(biphenyl-2-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.05 434

The examples in the following table (Table 5) were prepared in analogyto this procedure:

To 2-5 eq of boronic acid derivative were added 0.15 mmol2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate (0.25 M in NMP, 600 μL), 30 μmol1,1′-BIS(DIPHENYLPHOSPHINO)FERROCENE]DICHLOROPALLADIUM(II) (0.04 M inNMP, 750 μL) and 0.45 mmol potassium carbonate (1 M in water, 450 μL)and the mixture was heated in a microwave oven at 110° C. for 5 hours.After cooling, 0.9 mmol HCl (2M in water, 450 μL) were added and themixture was heated in a microwave oven for 10 hours at 50° C. Aftercooling, the mixture was filtered, washed with NMP and subjected topreparative HPLC to yield the target product.

LC-MS Method 4

TABLE 5 Retention LC-MS time m/z Example Structure Name [min] [M + H]⁺346

4-(2-chloropyridin-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.84 393.8 347

4-(1-benzothiophen-2-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 1.1  414.5 348

4-(1-methyl-1H-pyrazol-5- yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.71 362.4 349

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(quinolin-5-yl)-1,7-naphthyridine 0.74 409.5 350

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(pyridin-3-yl)-1,7-naphthyridine 0.66 359.4 351

4-(2-methoxypyridin-4-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.83 389.4 352

4-(5-methylpyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.7  373.4 353

4-(5-methoxypyridin-3-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.73 389.4 354

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(quinolin-3-yl)-1,7-naphthyridine 0.84 409.5 355

2-(morpholin-4-yl)-4-[1- (phenylsulfonyl)-1H-indol-2-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 1.12 537.6 356

4-(2-chloropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.77 393.8 357

4-(6-chloropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.82 393.8 358

{5-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]thiophen-2-yl}methanol 0.73 394.5 359

4-(2-fluoropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.75 377.4 360

4-(6-fluoropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.77 377.4 361

4-(2-chloro-6- methylpyridin-3-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.83 407.9 362

4-(2-methoxypyridin-3-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.79 389.4 363

4-(isoquinolin-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.77 409.5 364

4-(3-chloropyridin-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.79 393.8 365

4-(3-fluoropyridin-4-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.74 377.4 366

4-(2,6-difluoropyridin-3- yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.85 395.4 367

4-(1-methyl-1H-pyrazol-4- yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.67 362.4 368

tert-butyl 5-methoxy-2[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]-1H- indole-1-carboxylate 1.19 527.6 369

2-(morpholin-4-yl)-4-[6- (morpholin-4-yl)pyridin-3-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 0.76 444.5 370

4-(4-methylthiophen-3-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.9  378.5 371

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(thiophen-2-yl)-1,7-naphthyridine 0.87 364.4 372

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(thiophen-3-yl)-1,7-naphthyridine 0.83 364.4 373

4-(3-methylthiophen-2-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.93 378.5 374

4-(2-chloro-5- methylpyridin-3-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.84 407.9 375

4-(4-methoxypyridin-3-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.56 389.4 376

4-(5-chloro-2- methoxypyridin-3-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.96 423.9 377

tert-butyl 5-methyl-2-[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]-1H- indole-1-carboxylate 1.29 511.6 378

4-(5-chloro-2- fluoropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.91 411.8 379

4-(3,5-dimethyl-1,2- oxazol-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 0.77 377.4 380

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(quinolin-8-yl)-1,7-naphthyridine 0.81 409.5 381

4-(5-methylthiophen-2-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.95 378.5 382

4-(6-ethoxypyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.9  403.4 383

4-(2-ethoxypyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.85 403.4 384

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(quinolin-6-yl)-1,7-naphthyridine 0.74 409.5 385

4-(2-chlorothiophen-3-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.95 398.9 386

5-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin- 2-amine 0.53 374.4 387

2-(morpholin-4-yl)-4-(1H- pyrazol-3-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.66 348.4 388

4-(6-methylpyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.66 373.4 389

4-(1-methyl-1H-pyrrol-2- yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.82 361.4 390

5-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin- 2-ol 0.6  375.4 391

4-(5-chloropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.83 393.8 392

4-(3-chloro-2- methoxypyridin-4-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.93 423.9 393

4-(3-chlorothiophen-2-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.96 398.9 394

4-(5-fluoropyridin-3-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.76 377.4 395

4-[2- (methylsulfanyl)pyrimidin- 5-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.84 406.5 396

N-cyclopropyl-5-[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4- yl]pyrimidin-2-amine 0.74 415.5 397

4-(isoquinolin-5-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.68 409.5 398

N-methyl-5-[2-(morpholin- 4-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridin-4-yl]pyridine-2-carboxamide 0.71 416.4 399

N-tert-butyl-5-[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridine- 3-carboxamide 0.82 458.5 400

4-[5- (methylsulfanyl)pyridin-3- yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.82 405.5 401

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-(1H- pyrrolo[2,3-b]pyridin-4-yl)-1,7-naphthyridine 0.72 398.4 402

3-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]pyridin- 2-amine 0.55 374.4 403

methyl 4-[2-(morpholin-4- yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridin-4-yl]thiophene-2-carboxylate 0.88 422.5 404

4-[2-methoxy-5- (trifluoromethyl)pyridin-3- yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 1.02 457.4 405

2-(morpholin-4-yl)-4-[2- (propan-2-yloxy)pyridin-3-yl]-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 0.93 417.5 406

4-(5-chloro-6- ethoxypyridin-3-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 1.06 437.9 407

4-(1-tert-butyl-1H-pyrazol- 4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.85 404.5

The examples in the following table (Table 6) were prepared in analogyto this procedure:

To 2-5 eq of amine derivative were added 0.15 mmol2-(morpholin-4-yl)-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yltrifluoromethanesulfonate (0.25 M in NMP, 600 μL) and the mixture washeated at 70° C. overnight. After cooling, 1.5 mmol HCl (2M in water,750 μL) were added and the mixture was heated overnight at 50° C. Aftercooling, the mixture was subjected to preparative HPLC to yield thetarget product.

LC-MS Method 4

TABLE 6 Retention LC-MS time m/z Example Structure Name [min] [M + H]⁺408

2-(morpholin-4-yl)-4- (piperidin-1-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.83 365.4 409

1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]piperidin-4-ol 0.66 381.4 410

N-methyl-2-(morpholin-4- yl)-N-phenyl-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.85 387.4 411

{1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]pyrrolidin-2- yl}methanol 0.68 381.4 412

N-methyl-2-(morpholin-4- yl)-N-propyl-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.8  353.4 413

4-(azepan-1-yl)-2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.86 379.5 414

4-(3-methylpiperidin-1- yl)-2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridine 0.89 379.5 415

4-(4-methylpiperidin-1- yl)-2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-naphthyridine 0.89 379.5 416

1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]piperidine-3- carboxamide 0.66 408.5 417

4-(2,5-dihydro-1H-pyrrol- 1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.74 349.4 418

4-(3,4-dihydroquinolin- 1(2H)-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 0.93 413.5 419

4-(3,4-dihydroisoquinolin- 2(1H)-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridine 0.91 413.5 420

4-(1,3-dihydro-2H- isoindol-2-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.87 399.5 421

2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-4-[1,3,3- trimethyl-6-azabicyclo[3.2.1]oct-6-yl]- 1,7-naphthyridine 1   433.6 422

tert-butyl 1-[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]- prolinate 0.88 451.5 423

N-methyl-N-(2- methylpropyl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridin-4-amine 0.85 367.5 424

N-(3-fluorophenyl)-N- methyl-2-(morpholin-4- yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.87 405.4 425

4-(1,1-dioxido-1-thia-6- azaspiro[3.3]hept-6-yl)-2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7- naphthyridine 0.68 427.5 426

4-(3-fluoropiperidin-1-yl)- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridine 0.88 383.4 427

N-(2-fluorophenyl)-N- methyl-2-(morpholin-4- yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.96 405.4 428

1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]-prolinamide 0.66 394.4 429

{1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]piperidin-4- yl}methanol 0.75 395.5 430

4-(4-methoxypiperidin-1- yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.85 395.5 431

N-(4-fluorophenyl)-N- methyl-2-(morpholin-4- yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.97 405.4 432

N-methyl-1-[2- (morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-yl]- prolinamide 0.69 408.5 433

4-[4- (ethylsulfonyl)piperazin- 1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.8  458.6 434

4-[4- (methylsulfonyl)piperazin- 1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- naphthyridine 0.74 444.5 435

N-cyclopropyl-N-methyl- 2-(morpholin-4-yl)-8-(1H- pyrazol-5-yl)-1,7-naphthyridin-4-amine 0.85 351.4 436

N-(2,2-dimethylpropyl)- N-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-naphthyridin-4-amine 1.02 381.5 437

{1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7- naphthyridin-4-yl]piperidin-3- yl}methanol 0.79 395.5

The title compounds described in the example section were tested inselected biological assays one or more times. When tested more thanonce, data are reported as either average values or as median values,wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Expression of ATR/ATRIP in HEK 293-6E Cells:

The cDNAs encoding the protein sequences of full-length human ATRsequence (Q13535) with an N-terminally fused Flag tag as well as thefull-length human ATRIP (Q8WXE1) were optimized for expression ineukaryotic cells and synthesized by the GeneArt Technology at LifeTechnologies. Both cDNAs also encoded att-site sequences at the 5′ and3′ ends for subcloning into the following destination vectors using theGateway Technology: pD-MamA (an in-house derivate of the vector pEAKfrom EdgeBioSystems but with a human CMV promotor) which provides aN-terminal fusion of a GST-tag to the integrated gene of interest;pD-MamB (an in-house derivative of pTT5 from NRCC, Y. Durocher) whichprovides a N-terminal fusion of a STREP II-tag to the integrated gene.The cDNAs of ATR and ATR-DN were cloned into pD-MamA and the ATRIP-FLinto pD-MamB. The cDNA sequence of codon-optimized ATR including a GSTtag is described in SEQ ID No. 1 of the attached sequence listing, itscorresponding protein sequence in SEQ ID No. 3. The cDNA sequence ofcodon-optimized ATRIP including a STREP II tag is described in SEQ IDNo. 2, its corresponding protein sequence in SEQ ID No. 4.

Coexpression of ATR and ATRIP by Transient Transfection in HEK293-6ECells:

For transient transfection of HEK293-6E suspension cells a BiostatCultibag Bioreactor with 5 L culture volume (starting volume) in a 20 Lculture bag was used. The cells were cultured in F17 Medium (Gibco,Invitrogen, Cat#05-0092DK) with the following supplements Pluronic F68(10 mL/L of 10% solution, Gibco #24040), Gluta-Max (20 ml of 100×solution/L, L-Alanyl-Glutamine (200 mM, Invitrogen #25030), G418 (finalconcentration 25 μg/ml, PAA #P02-012). The applied culture conditionswere 37° C., rocking rate 18 rpm, pH 7.0, pO2 55%. At the day oftransfection the cell culture had reached a cell density of 1.6×10⁶cells/mL and a viability of 99%. For preparation of the transfectionsolution to 500 mL F17 medium (without the supplements) 4 mg of the ATRencoding plasmid, 1 mg of the ATRIP encoding plasmid and 10 mg PEI(Polyethylenimin, linear, Polysciences #23966, as 1 mg/mL stocksolution) were subsequently added, carefully mixed and incubated at roomtemperature for 15 min. This transfection solution was then added to the5 L cell culture in the culture bag. This cell culture was incubated for5 h and afterwards 5 L of F17 medium with the mentioned supplements wereadded and the rocking rate increased to 19 rpm. 48 h after transfectionthe cells were harvested by centrifugation (30 min., 1000 g, 15° C.) andthe cell pellets stored at −80° C.

Purification:

Purification of the ATR (Flag-Tag)/ATRIP(Strep-Tag) complex was achievedby affinity chromatography using anti-FLAG-resin (Sigma, #A220).

Cells were harvested by centrifugation (4000×g) and lysed in buffer A(50 mM Tris-HCl pH 7.5; 150 mM NaCl, 5% Glycerol, 1 mM Na3VO4, 1 mM NaF,10 mM β-glycerophosphate, 1% Tween 20; 0.1% NP40; Complete with EDTA)for 1 h at 4° C. The supernatant (20.000×g) was than bound toFlag-Agarose and eluted after several washing steps using Buffer B (50mM Tris-HCl pH7.4; 150 mM NaCl; 10% Glycerin, 200 μg/ml Flag Peptidesfrom Sigma, #F3290). Elution fractions were aliquoted and shock frozenusing liquid nitrogen. The final concentration of ATR in the finalpreparation was 250 μg/ml calculated densitrometrically using BSA as astandard in a Coomassie stained gel. The yield of copurified ATRIP wasfar below a 1:1 ratio compared to ATR but was essential for ATRactivity.

Tracer A3′,6′-bis(dimethylamino)-N-(4-{[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}butyl)-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-5-carboxamideStep a tert-butyl(4-{[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}butyl)carbamate

The starting material4-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]-1H-indole was synthesizedaccording to the literature (WO2008/125833). A solution of4-[4-chloro-6-(morpholin-4-yl)pyrimidin-2-yl]-1H-indole (980 mg, 3.11mmol), diisopropylethylamine (805 mg, 1.09 ml, 6.23 mmol) andN—BOC-1,4-diaminobutane (879 mg, 4.67 mmol) in 1-methyl-2-pyrrolidinone(24.5 ml) was stirred overnight at 150° C. The mixture was allowed tocool to ambient temperature. Ethyl acetate (50 ml) and brine (50 ml)were added, the layers were separated and the organic layer was washedwith brine (3×50 ml). The organic layer was dried over sodium sulphateand the solvent was removed under reduced pressure. The title compoundwas obtained as crude mixture (purity 40%, 2.37 g) and used withoutfurther purification in the next step.

Step bN-[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]butane-1,4-diamine

Tert-butyl(4-{[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}butyl)carbamate(2.37 g, 2.03 mmol) was dissolved in HCl/dioxane (4M, 20 ml) and stirredat ambient temperature for 10 minutes. Ethyl acetate (50 ml) and water(50 ml) were added and the phases separated. By addition of aqueous NaOH(2N, 50 ml) the pH of the aqueous layer was basified and extracted withethyl acetate (2×50 ml). The combined organic layers were dried oversodium sulphate and the solvent was removed under reduced pressure. Thetitle compound was obtained in 77% yield (770 mg) and used withoutfurther purification in the next step.

Step c3′,6′-bis(dimethylamino)-N-(4-{[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}butyl)-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-6-carboxamideand3′,6′-bis(dimethylamino)-N-(4-{[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]amino}butyl)-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-5-carboxamide

N-[2-(1H-indol-4-yl)-6-(morpholin-4-yl)pyrimidin-4-yl]butane-1,4-diamine(70 mg, 0.14 mmol) was dissolved in DMF (3 mL). DIPEA (74 μl, 0.43 mmol,3 eq.) and a mixture of commercially available5-carboxytetramethylrhodamine N-succinimidyl ester and6-carboxytetramethylrhodamine N-succinimidyl ester (75 mg, 0.14 mmol, 1eq.) were added sequentially. The mixture was stirred for 15 minutes atambient temperature and concentrated under reduced pressure. The twotitle compounds were separated by preparative HPLC (H₂O(NH₄OH)/CH₃CN:85:15 to 45:55).

Isomer 1 was obtained in 22% yield (25 mg). ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]: 1.56 (4H), 2.92 (12H), 3.49 (4H), 3.69 (4H), 5.53 (1H), 6.48(6H), 6.74 (1H), 7.06 (1H), 7.33 (2H), 7.43 (1H), 7.63 (1H), 8.03 (2H),8.15 (1H), 8.71 (1H), 11.11 (1H).

Isomer 2 was obtained in 34% yield (31 mg). ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]: 1.67 (4H), 2.93 (12H), 3.38 (4H), 3.52 (4H), 3.71 (4H), 5.58(1H), 6.47 (6H), 6.80 (1H), 7.09 (1H), 7.28 (1H), 7.36 (2H), 7.44 (1H),8.02 (1H), 8.22 (1H), 8.44 (1H), 8.83 (1H).

Isomer 2 was used as ligand for the ATR binding assay which is describedinfra.

Tracer B3′,6′-bis(dimethylamino)-N-[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butyl]-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-5-carboxamideStep a tert-butyl[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-yl}oxy)butyl]carbamate

2-[(3R)-3-Methylmorpholin-4-yl]-8-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1,7-naphthyridin-4-ol(0.41 g, 1.0 mmol, 1 eq.) was solubilized in DMF (12 mL).4-(Boc-amino)butyl bromide (0.53 g, 2.1 mmol, 2 eq.) and K₂CO₃ (0.72 g,5.2 mmol, 5 eq.) were added to the mixture. The reaction was stirred atambient temperature for 16 hours. The suspension was diluted with EtOAcand filtered. The organic phase was concentrated under reduced pressureand the crude material purified by flash chromatography (gradientHex/EtOAc 9/1 to 100% EtOAc). The desired product was obtained in 87%yield (0.52 g). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]: 1.14-1.24 (m, 3H),1.38 (s, 9H), 1.41-1.69 (m, 5H), 1.80-1.90 (m, 2H), 1.99 (s, 2H),2.30-2.42 (m, 1H), 3.03 (q, 2H), 3.10-3.29 (m, 2H), 3.40-3.52 (m, 1H),3.73 (d, 3H), 3.91-3.99 (m, 1H), 4.12 (t, 1H), 4.27 (t, 2H), 4.45-4.58(m, 1H), 6.01-6.13 (m, 1H), 6.75 (d, 1H), 6.84-6.95 (m, 2H), 7.60 (s,1H), 7.75 (d, 1H), 8.35 (d, 1H). LC-MS (Method A): m/z: [M+H]⁺=567,R_(t)=1.31 min.

Step b4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butan-1-amine

4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butan-1-amine(0.10 g, 0.18 mmol, 1 eq.) was solubilized in CH₂Cl₂ (1.1 mL) and TFAwas added (0.27 mL, 3.5 mmol, 20 eq.). The reaction was stirred atambient temperature for 30 minutes. The mixture was then quenched withsaturated NaHCO₃ solution and the suspension was filtered. The solid wasdried under reduced pressure and the desired compound was obtainedwithout further purification in quantitative yield. ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]: 1.27 (d, 3H), 1.73-1.84 (m, 2H), 1.88-1.97 (m, 2H),2.92 (s, 2H), 3.49-3.61 (m, 1H), 3.65-3.74 (m, 1H), 3.80-3.87 (m, 1H),4.02-4.09 (m, 1H), 4.11-4.19 (m, 1H), 4.30 (s, 2H), 4.56-4.65 (m, 1H),6.82 (s, 1H), 7.34-7.40 (m, 1H), 7.50-7.65 (m, 4H), 7.71 (d, 1H), 8.33(d, 1H), 13.31-13.41 (m, 1H).

Step c3′,6′-bis(dimethylamino)-N-[4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butyl]-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-5-carboxamide

4-({2-[(3R)-3-Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl}oxy)butan-1-amine(18 mg, 0.047 mmol, 1 eq.) was solubilized in DMF (1 mL). DIPEA (25 μL,0.14 mmol, 3 eq.) and a mixture of commercially available5-carboxytetramethylrhodamine N-succinimidyl ester and6-carboxytetramethylrhodamine N-succinimidyl ester (25 mg, 0.047 mmol, 1eq.) were added sequentially. The reaction was stirred for 15 minutes atambient temperature and concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC (H₂O(NH₄OH)/CH₃CN: 85:15 to45:55) and the desired compound was obtained in 49% yield (18 mg).¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]: 1.26 (d, 3H), 1.79-1.88 (m, 2H),1.92-2.02 (m, 2H), 2.94 (s, 12H), 3.46 (q, 2H), 3.52-3.60 (m, 1H),3.67-3.73 (m, 1H), 3.82 (d, 1H), 4.01-4.07 (m, 1H), 4.12-4.19 (m, 1H),4.34 (t, 2H), 4.56-4.64 (m, 1H), 6.44-6.53 (m, 6H), 6.83 (s, 1H), 7.32(d, 1H), 7.37 (br. s., 1H), 7.61 (s, 1H), 7.73 (d, 1H), 8.24 (dd, 1H),8.32 (d, 1H), 8.46 (s, 1H), 8.88 (t, 1H), 13.36 (br. s., 1H).

1. Binding Assay ATR

To determine of binding activity of the test compounds, full-lengthhuman ATR protein was expressed and purified together with ATRIP asdescribed above. Furthermore, a fluorescently labelled compound (eithertracer A or B as described above) was used as a tracer molecule.Detection of the binding event of the tracer was achieved bytime-resolved fluorescence energy transfer (TR-FRET). We used ananti-GST-Terbium antibody (CisBio) that binds to the GST-tag at theN-terminus of ATR-kinase. Excitation of Terbium with 337 nm lightresults in emission of fluorescent light with 545 nm. In case atetrameric complex has formed (antiGST-Tb+GST-ATR+Strp2-ATRIP+tracer),part of the energy will be transferred from the Terbium to thefluorophore that itself emits light of 570 nm. Displacement of thefluorescent tracer by a test compound leads to a reduction of theTR-FRET-signal.

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (MTP, Greiner Bio-One, Frickenhausen, Germany). To prepare theATR-working solution, ATR/ATRIP stock solution was diluted in assaybuffer [50 mM HEPES (pH 7.0), 10 mM MgCl2, 1 mM DTT, 0.01% (w/v) Igepal,0.01% (w/v) BSA] to 4.2 nM protein concentration (concentration may varyfrom lot to lot of protein preparation). AntiGST-Tb antibody was dilutedto 4.2 nM. The ATR-working solution was incubated for 30 min at 22° C.prior to dispensing to pre-form the complex of antiGST-Tb+GST-ATR+ATRIP.Then, 3 μl of the ATR-working solution were added to the test compoundand the mixture was incubated for 10 min at 22° C. to allow pre-bindingof the test compounds to ATR/ATRIP. Then, 2 μl of a 100 nM solution ofeither tracer A or B in assay buffer were added to the ATR-workingsolution. The resulting mixture was incubated for 30 min at 22° C. Themeasurement of the TR-FRET signal was performed in a standardHTRF-compatible MTP reader instrument (e.g. BMG Pherastar) by recordingthe fluorescence emissions at 545 nm and 570 nm after excitation at337-350 nm. The ratio between emission at 570 nm divided by emission at545 nm was calculated to give the well ratio. The experimental data(well ratios) were normalised by the following way: positive controlcontained ATR-working solution plus either tracer A or B solution (=0%inhibition), the negative control contained all components exceptGST-ATR/ATRIP (=100% inhibition). Usually the compounds were tested onthe same MTP in 11 different concentrations in the range of 20 μM to 0.1nM (20 μM, 5.9 μM, 1.7 μM, 0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1nM, 0.33 nM and 0.1 nM). The dilution series were prepared separatelybefore the assay on the level of the 100 fold concentrated solutions inDMSO by serial 1:3.4 dilutions in duplicate values for eachconcentration. IC₅₀ values were calculated by a 4 parameter fit usingstandard software (GraphPad prism or equivalent).

TABLE 7 ATR binding ATR binding (tracer A) ATR binding (tracer B)Example No IC₅₀ [M] IC₅₀ [M] 1 3.68E−8 2.39E−8 2 9.52E−8 3.83E−8 35.69E−8 3.87E−8 4 6.17E−8 4.35E−8 5 6.43E−8 3.41E−8 6 6.86E−8 7 5.87E−82.65E−8 8 1.18E−7 6.92E−8 9 1.20E−7 1.27E−7 10 1.26E−7 4.39E−8 111.35E−7 8.68E−8 12 1.35E−7 4.72E−8 13 1.41E−7 1.04E−7 14 1.62E−7 7.99E−815 1.63E−7 1.74E−7 16 1.73E−7 17 1.85E−7 1.17E−7 18 2.28E−7 7.51E−8 192.93E−7 1.81E−7 20 8.16E−7 3.20E−7 21 1.90E−7 22 4.65E−7 23 4.43E−7 243.82E−8 2.07E−8 25 1.10E−7 7.51E−8 26 1.56E−8 6.36E−9 27 1.72E−8 1.09E−828 1.76E−8 8.40E−9 29 2.15E−8 9.23E−9 30 2.28E−8 9.48E−9 31 8.66E−84.51E−8 32 8.47E−8 3.67E−8 33 1.98E−8 1.03E−8 34 3.57E−7 5.36E−7 351.22E−7 7.55E−8 36 1.50E−6 37 1.70E−7 1.27E−7 38 5.02E−7 4.05E−7 396.01E−8 3.53E−8 40 1.25E−7 9.90E−8 41 3.39E−7 2.30E−7 42 4.84E−7 5.33E−743 4.93E−7 2.58E−7 44 5.43E−7 3.27E−7 45 2.93E−7 46 2.62E−7 47 1.39E−648 1.61E−7 49 2.00E−7 50 4.10E−7 5.14E−7 51 3.80E−8 2.33E−8 52 1.01E−77.89E−8 53 1.92E−7 6.35E−8 54 2.88E−7 1.29E−7 55 1.62E−7 56 7.51E−73.24E−7 57 2.30E−7 58 4.13E−7 6.15E−7 59 7.30E−7 1.25E−6 60 2.41E−81.57E−8 61 7.09E−7 5.03E−7 62 9.97E−7 7.07E−7 63 8.07E−8 3.07E−8 642.74E−8 65 3.35E−7 2.76E−7 66 8.72E−8 67 1.00E−6 1.27E−6 68 5.89E−74.72E−7 69 5.34E−9 70 5.17E−9 71 5.65E−9 72 6.33E−9 73 6.71E−9 747.10E−9 75 6.97E−9 76 8.91E−9 77 8.92E−9 78 1.10E−8 79 1.20E−8 801.21E−8 81 1.43E−8 82 4.90E−9 83 5.38E−9 84 6.60E−9 85 1.19E−8 861.09E−8 87 8.71E−9 88 1.53E−8 89 8.11E−9 90 1.06E−8 91 1.00E−8 921.37E−8 93 1.09E−8 94 1.37E−8 95 1.13E−8 96 1.27E−8 97 1.39E−8 981.31E−8 99 6.38E−9 100 1.65E−8 101 1.13E−8 102 1.23E−8 103 1.01E−8 1041.41E−8 105 8.67E−9 106 1.31E−8 107 1.37E−8 108 1.15E−8 109 9.14E−9 1101.35E−8 111 7.24E−9 112 4.74E−9 113 5.71E−9 114 7.35E−9 115 7.44E−9 1169.51E−9 117 8.16E−9 118 1.01E−8 119 1.17E−8 120 1.31E−8 121 1.74E−8 1221.94E−8 123 2.13E−8 124 1.36E−8 125 1.72E−8 126 2.15E−8 127 2.55E−8 1283.26E−8 129 3.53E−8 130 2.16E−8 131 2.31E−8 132 2.37E−8 133 2.70E−8 1343.43E−8 135 3.29E−8 136 3.58E−8 137 2.60E−8 138 2.90E−8 139 4.17E−8 1407.65E−8 141 3.86E−7 142 4.41E−8 143 2.77E−8 144 7.51E−8 145 1.82E−8 1463.57E−8 147 4.54E−8 148 4.79E−8 149 4.84E−8 150 5.03E−8 151 5.12E−82.32E−8 152 5.18E−8 153 5.47E−8 154 5.50E−8 155 6.33E−8 156 8.01E−8 1579.18E−8 158 1.35E−8 159 1.65E−8 160 3.72E−8 161 6.26E−8 162 1.00E−7 1631.07E−7 164 1.61E−7 165 2.24E−7 166 3.65E−7 167 4.08E−7 168 5.30E−7 1691.15E−7 170 1.68E−7 171 9.47E−8 172 8.28E−8 173 2.05E−7 174 2.13E−7 1752.21E−7 176 2.23E−7 177 2.50E−7 178 3.77E−7 179 4.54E−7 180 4.87E−7 1815.39E−7 182 6.32E−7 183 6.49E−7 184 7.63E−7 185 8.52E−7 186 6.74E−8 1879.68E−8 188 2.51E−7 189 2.14E−8 190 9.50E−9 191 4.41E−8 192 1.15E−7 1932.45E−7 194 3.76E−8 195 7.14E−8 196 7.26E−8 197 7.24E−8 198 2.93E−7 1991.38E−7 200 8.69E−8 201 4.00E−8 202 7.83E−8 203 1.13E−8 204 6.76E−9 2054.93E−8 206 4.04E−7 207 5.42E−7 208 1.16E−6 209 3.85E−7 210 2.31E−7 2115.47E−7 212 >2.00E−5  213 5.35E−8 214 1.76E−7 215 3.17E−7 216 8.44E−8217 8.02E−7 218 1.18E−8 219 1.32E−7 220 3.24E−8 221 1.96E−7 222 5.02E−8223 1.24E−7 224 5.21E−8 225 4.47E−7 226 1.14E−6 227 7.55E−8 228 3.01E−8229 2.84E−8 230 3.17E−8 232 3.91E−8 233 4.20E−8 234 2.92E−8 235 2.13E−8236 2.82E−8 237 1.82E−8 238 3.45E−8 239 2.03E−8 240 3.00E−8 241 4.06E−9242 9.59E−8 243 3.65E−8 244 1.59E−7 245 3.20E−8 246 6.80E−8 247 2.16E−8248 2.41E−8 249 1.37E−8 250 6.62E−9 251 2.75E−8 252 6.45E−9 253 3.37E−8254 4.48E−8 255 4.27E−8 256 5.62E−8 257 5.88E−8 258 7.66E−9 259 1.71E−8260 2.81E−8 261 2.92E−8 262 4.22E−8 263 1.93E−8 264 2.55E−8 265 7.46E−8266 8.31E−9 267 1.01E−6 268 1.93E−8 269 1.27E−8 270 3.37E−8 271 4.16E−8272 2.13E−8 273 1.40E−8 274 6.27E−8 275 3.04E−7 276 2.37E−7 277 7.82E−8278 2.69E−8 279 2.93E−7 280 4.68E−8 281 1.36E−8 282 1.27E−8 283 3.37E−8284 4.16E−8 285 5.09E−7 286 1.45E−8 287 6.75E−7 4.61E−7 288 3.45E−7 2892.99E−6 290 1.19E−6 291 8.37E−8 292 1.08E−7 293 3.28E−7 294 3.72E−8 2951.13E−7 296 7.68E−8 297 1.19E−7 298 5.92E−8 299 5.52E−8 300 1.81E−7 3012.16E−8 302 1.88E−7 303 8.61E−8 304 5.72E−8 305 1.33E−7 306 8.23E−8 3071.89E−7 308 1.31E−7 309 1.46E−7 310 9.77E−8 311 3.76E−7 312 2.37E−8 3132.90E−8 314 6.79E−8 316 5.32E−8 317 6.65E−8 318 3.06E−8 319 3.25E−7 3204.68E−8 321 4.44E−8 322 8.09E−8 324 7.77E−8 325 3.44E−8 326 7.32E−8 3271.77E−8 328 2.96E−7 329 1.69E−7 330 9.13E−8 331 3.76E−7 332 6.81E−8 3332.53E−8 334 5.81E−8 335 6.62E−8 336 1.20E−7 337 2.84E−8 338 1.03E−7 3398.96E−8 340 3.35E−8 341 2.64E−8 342 2.77E−6 343 1.98E−8 344 1.74E−7 3455.56E−8 346 1.40E−7 347 2.41E−7 348 5.53E−8 349 1.19E−7 350 1.62E−7 3511.54E−7 352 1.75E−7 353 2.42E−7 354 8.47E−8 355 4.84E−7 356 7.95E−8 3575.35E−8 358 4.64E−8 359 8.55E−8 360 9.38E−8 361 5.22E−8 362 2.95E−7 3631.91E−7 364 5.64E−8 365 1.03E−7 366 5.21E−8 367 2.15E−7 368 3.95E−6 3691.15E−7 370 3.50E−8 371 1.22E−7 372 1.34E−7 373 3.81E−8 374 1.36E−7 3758.94E−7 376 3.57E−7 377 2.99E−6 378 9.27E−8 379 6.98E−8 380 1.46E−6 3811.21E−7 382 1.99E−7 383 2.39E−7 384 8.92E−8 385 8.51E−8 386 1.73E−7 3872.18E−7 388 7.91E−8 389 2.66E−8 390 6.63E−7 391 1.76E−7 392 4.43E−8 3934.15E−8 394 1.19E−7 395 1.49E−7 396 1.74E−7 397 9.55E−8 398 1.20E−7 3996.18E−7 400 3.00E−7 401 8.75E−8 402 2.99E−7 403 1.94E−7 404 4.24E−7 4054.19E−7 406 3.64E−7 407 3.09E−7 408 6.51E−8 409 1.39E−7 410 1.53E−7 4121.62E−7 413 2.79E−7 414 9.08E−8 415 3.27E−8 416 2.51E−7 417 1.07E−6 4189.41E−8 419 1.18E−7 420 6.02E−7 421 1.79E−6 422 2.24E−6 423 8.39E−8 4242.41E−7 425 1.00E−6 426 1.59E−7 427 1.12E−7 428 6.98E−8 429 4.48E−8 4306.13E−8 431 3.47E−8 432 2.04E−6 433 4.16E−8 434 3.18E−8 435 6.51E−8 4362.40E−8 437 1.18E−7

2. ATR Activity Assay

ATR kinase phosphorylates a biotinylated peptide derived from Rad17(sequence: biotin-PEG2-ASELPASQPQPFS-amide, produced by Biosyntan GmbH,Berlin). The assay measures the amount of phosphorylated peptide bytime-resolved fluorescence (TR-FRET). Streptavidin-XL665 (Cisbio,reference #610SAXLB), an anti-Rad17-phospho-serine 645 specific antibody(available from either Imgenex/Biomol, reference #IMG-6386A, or fromLifespan, reference #LS-C43028) and antiRabbit-IgG-Europium (PerkinElmer, reference #AD0083) are employed to specifically detectphosphorylated biotin-peptide, but not non-phosphorylated peptide.Excitation of Europium with 337 nm light results in emission offluorescent light with 620 nm. In case a tetrameric detection complexhas formed, part of the energy will be transferred to theStreptavidin-XL665 fluorophor that itself emits light of 665 nm.Unphosphorylated peptide does not give rise to light emission at 665 nm,because no FRET-competent detection complex can be formed.

For the assay 50 nl of a 100-fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384well microtiterplate (MTP, Greiner Bio-One, Frickenhausen, Germany). To prepare theATR-working solution, ATR/ATRIP stock solution (expression andpurification: see above) was diluted in assay buffer [50 mM HEPES (pH7.0), 10 mM MgCl2, 1 mM dithiothreitol (DTT), 0.01% (w(v) Igepal, 0.2%(w/v) bovine gamma globulin (BGG)] to 10 nM protein concentration(concentration may vary from lot to lot of protein preparation). Asubstrate working solution was prepared by diluting the biotinylatedRad17 peptide to 0.5 μM together with ATP to 20 μM in assay buffer. Astop/detection working solution was prepared containing 50 mM Hepes pH7.0, 0.15% (w/v) bovine serum albumin (BSA), 150 mM EDTA, 200 nMStreptavidin-XL665, 2.5 nM anti phospho Rad17-pS645 (IMG-6386A) and 1.5nM anti-Rabbit-IgG-Eu. The amount of the antibodies is dependent on thebatch used and was optimized by variation the activity of the batch. Allsolutions were kept at 20° C. First, 2.5 μl of ATR-working solution weredispensed into the wells of the MTP containing the test compounds. After10 minutes pre-incubation to allow binding of the compounds to ATR, 2.5μl of substrate working solution was dispensed to the wells. After 180minutes, 5 μl of stop/detection solution were dispensed into the wells.The resulting mixture was incubated for 60 min at 20° C. The measurementof the TR-FRET signal was performed in a standard HTRF-compatible MTPreader instruments (e.g. BMG Pherastar or Perkin Elmer ViewLux) byrecording the fluorescence emissions at 620 nm and 665 nm afterexcitation at 337-350 nm. The ratio between emission at 665 nm dividedby emission at 620 nm was calculated to give the well ratio. Theexperimental data (well ratios) were normalised by the following way:positive control was composed of ATR-working solution+substrate solution(=0% inhibition), the negative control contains the same reagents, butATR-working solution is replaced by assay buffer (=100% inhibition).Usually the compounds were tested on the same MTP in 11 differentconcentrations in the range of 20 μM to 0.1 nM (20 μM, 5.9 μM, 1.7 μM,0.51 μM, 0.15 μM, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1 nM) Thedilution series were prepared separately before the assay on the levelof the 100 fold concentrated solutions in DMSO by serial 1:3.4 dilutionsin duplicate values for each concentration. IC₅₀ values were calculatedby a 4 parameter fit using with standard software (GraphPad prism orequivalent).

3. Proliferation Assay

Human tumour cells (Table 8) were originally obtained from the AmericanType Culture Collection (ATCC), the Deutsche Sammlung vonMikroorganismen and Zellkulturen (DSMZ, German Collection ofMicroorganisms and Cell Cultures), or Epo GmbH Berlin. Adherentlygrowing cells (HeLa, HeLa-MaTu-ADR, HT-144, Lovo, HT-29, NCI-H460,DU145, Caco2, B16F10) were plated out in a density of 1500-4000cells/measurement point, depending on the rate of growth of the cellline, in a 96-well multititre plate in 200 μl of growth medium(DMEM/HAMS F12, 2 mM L-glutamine, 10% foetal calf serum). After 24hours, the cells of one plate (zero plate) were dyed with crystal violet(see below), whereas the medium of the other plates was replaced withfresh culture medium (200 μl) to which the test substances were added invarious concentrations (0 μM, and also in the range of 0.001-10 μM; thefinal concentration of the solvent dimethyl sulphoxide was 0.1 or 0.5%).The cells were incubated for 4 days in the presence of the testsubstances. Cell proliferation was determined by staining the cells withcrystal violet: the cells were fixed at room temperature for 15 min byadding 20 μl/measurement point of an 11% strength glutaraldehydesolution. After washing the fixed cells three times with water, theplates were dried at room temperature. The cells were stained by adding100 μl/measurement point of a 0.1% strength crystal violet solution (pHadjusted to pH 3 by adding acetic acid). After washing the cells threetimes with water, the plates were dried at room temperature. The dye wasdissolved by adding 100 μl/measurement point of a 10% strength aceticacid solution. Absorbance was determined photometrically at a wavelengthof 595 nm. The percentage change in cell growth was calculated bynormalizing the measured values to the absorbance values of the zeroplate (=0%) and the absorbance of the untreated (0 W) cells (=100%). TheIC₅₀ values were determined by means of a four parameter fit.

Cells growing in suspension (GRANTA-519, Jeko-1) were plated out in acell density of 2000-4000 cells/measurement point, depending on the rateof growth of the cell line, in a black-walled, clear-bottom 96-wellmultititre plate in 100 μl of growth medium (DMEM/HAMS F12, 2 mML-glutamine, 10% foetal calf serum). After 24 hours, cell density wasdetermined in one plate (zero plate) by adding 60 μl/measurement pointof CTG solution (Promega Cell Titer-Glo solution (catalogue numbersG755B and G756B)), subsequent incubation for 2 min followed by 10 minshaking (in the dark) and measurement of luminescence (VICTOR V, PerkinElmer).

For the test plates, the test substances were prepared in variousconcentrations (0 μM, and also in the range of 0.001-10 μM; the finalconcentration of the solvent dimethyl sulphoxide was 0.1 or 0.5%) as 3×concentrated solutions in fresh growth medium. Aliquots of 50 μl eachwere added to the cell suspensions and the cells were incubated for 4days in the presence of the test substances. Subsequently, cell densitywas determined using CTG solution as described above and IC₅₀ valueswere calculated by means of a four parameter fit.

The substances were investigated in the following cell lines, which, byway of example, represent the specified indications (Table 8).

TABLE 8 List of the cell lines investigated in the proliferation assays.Tumour indication Cell line Source Cervical cancer HeLa DSMZ ACC-57HeLa-MaTu-ADR Epo GmbH (multi-drug resistant) Colon & colorectal cancerLovo DSMZ ACC-500 HT29 DSMZ ACC-299 Caco-2 DSMZ ACC-169 Lymphoma, mantlecell GRANTA-519 DSMZ ACC-342 Jeko-1 DSMZ ACC-553 Melanoma, malignantHT-144 ATCC HTB-63 B16F10 ATCC CRL-6475 Non-small cell lung cancerNCI-H460 ATCC HTB-177 Prostate cancer (hormone DU145 DSMZ ACC-261independent)

The results of the proliferation assays demonstrate the efficacy of testcompounds in the human tumour cells investigated. These data suggest apossible use of the test compounds in the tumour types investigated.

TABLE 9 Inhibition of proliferation of HeLa, HeLa-MaTu-ADR, NCI-H460,DU145, Caco-2 and B16F10 cells by compounds according to the presentinvention, determined as described above. All IC₅₀ (inhibitoryconcentration at 50% of maximal effect) values are indicated in M,“n.t.” means that the compounds have not been tested in the respectiveassay. Table 9: Inhibition of proliferation {circle around (1)} {circlearound (2)} {circle around (3)} {circle around (4)} {circle around (5)}{circle around (6)} {circle around (7)} 3 2.77E−6 5 >3.00E−6 6.41E−73.68E−7 2.19E−6 2.98E−6 6 1.49E−6 7 1.33E−6 2.31E−6 1.02E−6 1.59E−65.95E−6 2.98E−6 >1.00E−5 8.97E−6 8 2.26E−6 >3.00E−6 9.09E−72.05E−6 >3.00E−6 >3.00E−6 9 1.01E−6 10 4.96E−7 1.30E−6 4.47E−7 8.27E−71.46E−6 2.98E−6 11 >1.00E−5 3.05E−6 2.28E−6 14 1.99E−6 151.41E−6 >3.00E−6 5.28E−7 8.17E−7 1.72E−6 >3.00E−6 24 3.41E−6 3.78E−71.35E−6 8.33E−7 3.65E−6 26 2.96E−7 >1.00E−6 5.86E−77.25E−7 >1.00E−6 >1.00E−6 27 3.55E−7 28 3.16E−7 29 3.94E−7 4.98E−72.43E−7 2.91E−7 5.77E−7 1.58E−6 30 5.12E−7 >3.00E−6 2.93E−7 3.25E−72.89E−6 1.37E−6 31 1.25E−6 >3.00E−6 6.85E−7 1.11E−6 >3.00E−6 >3.00E−6 321.56E−6 >3.00E−6 >3.00E−6 1.84E−6 >3.00E−6 >3.00E−6 1.95E−6 33 >3.00E−62.69E−7 1.01E−6 6.53E−7 1.08E−6 34 1.02E−6 >3.00E−6 1.63E−6 2.39E−64.99E−6 >3.00E−6 37 5.08E−6 39 1.05E−6 4.00E−7 8.37E−7 40 2.72E−62.26E−6 6.72E−7 1.15E−6 1.97E−6 2.82E−6 >3.00E−6 43 3.88E−6 441.01E−6 >1.00E−5 2.01E−6 4.45E−6 7.69E−6 >1.00E−5 50 >1.00E−5 >1.00E−551 1.23E−6 1.80E−6 3.91E−7 8.95E−7 2.93E−6 >3.00E−6 53 1.41E−6 576.98E−6 3.74E−7 1.56E−6 5.51E−7 6.32E−6 >3.00E−6 >3.00E−6 >3.00E−6 609.98E−7 2.17E−6 6.91E−7 7.30E−7 1.98E−6 >3.00E−6 621.64E−7 >3.00E−6 >3.00E−6 >3.00E−6 <3.00E−8 1.31E−7 1.13E−6 >3.00E−62.29E−7 >3.00E−6 2.18E−5 >3.00E−6 63 1.53E−6 3.08E−7 9.15E−7 1.54E−62.19E−6 64 1.17E−6 9.23E−8 5.06E−7 8.44E−7 8.76E−7 66 8.90E−6 1.27E−77.26E−7 3.35E−6 2.98E−6 >3.00E−6 >3.00E−6 69 1.91E−7 70 2.01E−7 711.67E−7 72 2.00E−7 73 1.81E−7 1.79E−6 5.90E−8 7.48E−7 6.31E−7 6.04E−7 742.03E−7 >1.00E−6 >1.00E−6 >1.00E−6 >1.00E−6 >1.00E−6 75 2.71E−7 769.68E−7 77 2.54E−7 78 6.55E−7 79 3.03E−7 2.30E−6 9.37E−8 6.56E−7 8.68E−71.06E−6 80 1.87E−7 81 2.45E−7 82 5.29E−7 83 3.31E−7 84 1.30E−7 854.38E−7 87 5.43E−7 88 1.57E−7 2.91E−7 8.17E−8 1.04E−7 2.86E−7 4.98E−7 891.42E−7 90 9.20E−8 91 1.08E−7 92 1.17E−7 93 1.79E−7 94 2.68E−7 952.11E−7 96 1.69E−7 97 2.52E−7 98 4.40E−7 99 4.00E−7 100 9.50E−7 1013.41E−7 102 6.04E−7 103 3.74E−7 104 4.99E−7 105 1.00E−6 106 4.34E−7 1073.06E−7 108 4.56E−7 109 2.98E−7 110 2.06E−7 111 1.56E−7 2.26E−7 6.50E−81.10E−7 2.37E−7 7.11E−7 112 9.95E−8 113 1.22E−7 114 1.77E−7 115 1.99E−7116 2.84E−7 117 2.25E−7 118 1.71E−7 119 4.25E−7 120 3.54E−7 121 3.52E−7122 7.06E−7 123 4.31E−7 124 1.56E−7 125 7.05E−7 >3.00E−6 5.61E−77.12E−7 >3.00E−6 >3.00E−6 >3.00E−6 5.41E−7 7.64E−7 2.63E−6 >3.00E−6 1261.70E−7 5.95E−7 8.84E−8 9.40E−8 3.40E−7 9.06E−7 127 5.78E−7 128 7.70E−7129 6.86E−7 130 3.74E−7 131 3.49E−7 132 5.07E−7 133 1.07E−6 134 1.53E−6135 1.82E−6 136 5.75E−7 137 3.83E−7 7.91E−7 1.53E−7 1.46E−7 5.49E−77.79E−7 138 6.19E−7 139 1.37E−6 142 1.59E−6 143 5.43E−7 144 >3.00E−6 1452.48E−7 5.22E−7 9.06E−8 3.05E−8 4.92E−7 1.09E−6 146 1.11E−6 147 9.53E−7148 8.05E−7 151 9.21E−7 2.15E−6 6.73E−7 1.90E−6 2.05E−6 2.13E−6 1526.71E−7 153 7.59E−7 155 9.59E−7 156 1578.72E−7 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6 >3.00E−6158 3.28E−7 159 6.16E−8 160 4.51E−7 161 5.88E−7 162 1.22E−6 1697.31E−7 >3.00E−6 2.62E−6 2.82E−6 >3.00E−6 >3.00E−6 >3.00E−6 5.62E−75.91E−7 >3.00E−6 >3.00E−6 170 2.41E−6 172 2.10E−6 173 >3.00E−6 1762.52E−6 177 >3.00E−6 178 >3.00E−6 179 >3.00E−6 185 >3.00E−6 186 7.89E−7189 1.01E−6 190 3.34E−7 191 2.12E−6 194 8.92E−7 195 3.01E−6 1961.02E−6 >3.00E−6 2.91E−7 1.44E−7 8.69E−7 1.47E−6 197 1.01E−6 >3.00E−65.16E−7 1.29E−7 >3.00E−6 2.96E−6 198 >3.00E−6 199 8.57E−7 9.65E−73.20E−7 2.44E−7 7.08E−7 >1.00E−6 200 1.96E−6 201 >3.00E−6 202 1.53E−6203 9.98E−7 204 5.68E−7 205 6.72E−7 1.49E−6 2.19E−7 6.52E−7 1.24E−61.70E−6 213 >3.00E−6 214 >3.00E−6 215 >3.00E−6 216 1.01E−6 >3.00E−61.11E−6 1.66E−6 >3.00E−6 >3.00E−6 >3.00E−6 1.02E−61.33E−6 >3.00E−6 >3.00E−6 218 3.00E−7 219 2.98E−6 220 6.04E−7 9.93E−73.03E−7 3.34E−7 >1.00E−6 >1.00E−6 221 >3.00E−6 222 9.75E−7 227 1.94E−6228 2.25E−7 5.94E−7 2.33E−7 3.13E−7 6.37E−7 2.60E−6 229 4.47E−7 2303.80E−7 232 3.41E−7 233 1.80E−7 234 1.21E−6 235 9.50E−7 236 7.92E−7 2375.28E−7 238 1.18E−6 239 1.13E−6 241 1.71E−7 242 8.11E−7 243 3.60E−7 2453.43E−7 246 2.84E−6 247 2.28E−7 248 4.51E−7 249 4.09E−7 250 1.16E−7 2518.00E−7 252 2.22E−7 253 5.58E−7 254 3.12E−7 255 4.58E−7 258 2.63E−7 2594.97E−7 260 4.85E−7 261 4.20E−7 262 4.71E−7 263 3.32E−7 264 1.98E−7 2661.54E−7 267 2.97E−6 268 4.15E−7 269 4.05E−7 270 5.65E−7 271 1.33E−6 2726.48E−7 273 9.99E−7 274 6.10E−7 277 4.01E−7 278 1.68E−7 280 4.17E−7 2812.59E−7 282 1.18E−6 283 1.46E−7 284 8.52E−7 286 2.93E−7 8.82E−7 7.56E−84.86E−8 5.29E−7 5.86E−7 291 1.52E−6 292 2.64E−6 294 2.45E−6 296 2.74E−6298 2.44E−6 299 >3.00E−6 301 2.82E−6 303 >3.00E−6 304 >3.00E−6306 >3.00E−6 310 >3.00E−6 312 >3.00E−6 313 2.54E−6 314 >3.00E−6316 >3.00E−6 317 2.98E−6 318 2.00E−6 320 >3.00E−6 321 >3.00E−6322 >3.00E−6 323 2.22E−6 324 2.42E−6 325 9.99E−7 326 2.92E−6 327 1.89E−6330 >3.00E−6 332 >3.00E−6 333 >3.00E−6 334 >3.00E−6 335 2.96E−6 3371.71E−6 339 >3.00E−6 340 2.95E−6 341 1.59E−6 343 1.71E−6 345 >3.00E−6348 6.13E−7 9.40E−7 3.99E−7 5.18E−7 8.22E−7 2.22E−6 349 >3.00E−6350 >3.00E−6 351 3.00E−6 {circle around (1)}Example Number {circlearound (2)}Inhibition of HeLa cell proliferation {circle around(3)}Inhibition of HeLa-MaTu-ADR cell proliferation {circle around(4)}Inhibition of NCI-H460 cell proliferation {circle around(5)}Inhibition of DU145 cell proliferation {circle around (6)}Inhibitionof Caco-2 cell proliferation {circle around (7)}Inhibition of B16F10cell proliferation

4. Phospho-H2AX Assay

Phospho-Ser139 Histone H2AX (also known as

H2AX, UniProtKB/Swiss-Prot P16104) represents an cellular early markerfor DNA damage response. In particular, H2AX gets phosphorylated by ATRupon DNA replication stress. HT-29 human colorectal adenoadenocarcinomacells, originally obtained from the DSMZ, were plated out in a densityof 12000 cells/measurement point a black-walled, clear-bottom 96-wellmultititre plate in 100 μl of growth medium (DMEM/HAMS F12, 2 mML-glutamine, 10% foetal calf serum). After 24 hours, the test substanceswere added in various concentrations (0 μM, and also in the range of0.001-10 μM in quadruplicates; the final concentration of the solventdimethyl sulphoxide was 0.1%) followed by addition of a hydroxyureasolution to achieve a finale concentration of 2.5 mM and a final assayvolume of 200 μL. One control plate was left untreated and furtherprocessed in parallel. The cells were incubated for 30 min at 37° C.Subsequently, the growth medium was carefully evaporated and the cellswere fixed with 50 μL/well of ice-cold methanol for 15 min. The cellswere washed once with 100 μL/well of PBS, followed by incubation with 50μL/well of blocking buffer (Liqor, 927-40000) for 1 h at roomtemperature. Subsequently, the cells were incubated with 50 μL/well ofanti-phospho-H2AX (Ser 139) antibody (Merck Millipore, clone JBW301,05-636) diluted 1:500 in blocking buffer for 1 h at room temperature (orover night at 4° C.). The cells were washed three time with 100 μL/wellof PBS, followed by incubation with 50 μL/well of a 1:500 dilutedsolution of Alexa Fluor 488 conjugated donkey anti-mouse IgG antibody(Life Technologies, A-21202) in TBST for 1 h at room temperature andprotected from light. After the cells were washed three time with 100μL/well of PBS, the wells were filled with 100 μL of PBS andfluorescence was determined using an Acumen laser scanning cytometer(TTP Labtech). The percentage change in hydroxy urea inducedphospho-H2AX content was calculated by normalizing the measured valuesto the fluorescence values of untreated control wells (=0%) and thefluorescence of the hydroxy urea control wells without test compounds (0μM, =100%). The IC₅₀ values were determined by means of a four parameterfit.

5. Caco-2 Permeation Assay

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded ata density of 4.5×104 cell per well on 24 well insert plates, 0.4 μm poresize, and grown for 15 days in DMEM medium supplemented with 10% fetalbovine serum, 1% GlutaMAX (100×, GIBCO), 100 U/ml penicillin, 100 μg/mlstreptomycin (GIBCO) and 1% non essential amino acids (100×). Cells weremaintained at 37° C. in a humified 5% CO2 atmosphere. Medium was changedevery 2-3 day.

Before running the permeation assay, the culture medium was replaced bya FCS-free hepes-carbonate transport puffer (pH 7.2) For assessment ofmonolayer integrity the transepithelial electrical resistance (TEER) wasmeasured. Test compounds were predissolved in DMSO and added either tothe apical or basolateral compartment in final concentration of 2 μM.Before and after 2 h incubation at 37° C. samples were taken from bothcompartments. Analysis of compound content was done after precipitationwith methanol by LC/MS/MS analysis. Permeability (Papp) was calculatedin the apical to basolateral (A→B) and basolateral to apical (B→A)directions. The apparent permeability was calculated using followingequation:

Papp=(Vr/Po)(1/S)(P2/t)

Where Vr is the volume of medium in the receiver chamber, Po is themeasured peak area of the test drug in the donor chamber at t=o, S thesurface area of the monolayer, P2 is the measured peak area of the testdrug in the acceptor chamber after 2 h of incubation, and t is theincubation time. The efflux ratio basolateral (B) to apical (A) wascalculated by dividing the Papp B-A by the Papp A-B. In addition thecompound recovery was calculated. As assay control reference compoundswere analyzed in parallel.

1. A method of using an intermediate compound for the preparation of acompound of general formula (Ib):

in which: R¹ represents

wherein * indicates the point of attachment of said group with the restof the molecule; R² represents hydrogen, halogen, —NR⁷R⁸, CN,C₁-C₆-alkyl, C₁-C₄-alkoxy, 3- to 10-membered heterocycloalkoxy,C₂-C₄-alkenyl, C₃-C₆-cycloalkyl, 3- to 10-membered heterocycloalkyl, 4-to 10-membered heterocycloalkenyl, phenyl, heteroaryl, —(CO)NR⁷R⁸,—(SO₂)R⁹, —(SO)R⁹, —SR⁹, —N═(SO)R⁹R¹⁰, —(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰ or—(PO)(R¹⁰)₂; wherein each C₁-C₆-alkyl, C₁-C₄-alkoxy, C₃-C₆-cycloalkyl,3- to 10-membered heterocycloalkyl, phenyl or heteroaryl is optionallysubstituted, one or more times, independently from each other, withhalogen, OH, amino, —NR⁷R⁸, C₁-C₄-alkyl optionally substituted withhydroxyl or phenyl, C₁-C₂-haloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyl, 3-to 6-membered heterocycloalkyl, phenyl, —(CO)OR⁷, —(CO)NR⁷R⁸,—NR⁷(CO)R¹⁰, —NR⁸(CO)OR⁷, —(SO₂)R⁹, —SR⁹, —NR⁷(SO₂)R⁹, —((SO)═NR¹¹)R¹⁰,—(PO)(OR⁷)₂, —(PO)(OR⁷)R¹⁰ or a heteroaryl group; wherein each 4- to10-membered heterocycloalkenyl is optionally substituted, one or moretimes, independently from each other, with methyl; R⁴ representshydrogen or methyl; R⁷, R⁸ represent, independently from each other,hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl or phenyl, wherein phenyl isoptionally substituted, one or more times, with halogen; R⁹ representsC₁-C₄-alkyl or phenyl, wherein each C₁-C₄-alkyl or phenyl is optionallysubstituted, one or more times, independently from each other, with R³³;R¹⁰ represents C₁-C₄-alkyl; or R⁹ and R¹⁰ together, in case of—N═(SO)R⁹R¹⁰ group, represent a 5- to 8-membered heterocycloalkyl group;R¹¹ represents hydrogen, C₁-C₄-alkyl, —(CO)OR⁷, —(CO)NR⁷R⁸ or CN; R¹³represents halogen, OH or C₁-C₆-alkoxy; wherein the intermediatecompound is selected from the group consisting of:

in which R³ represents hydrogen; X represents chloro, bromo or iodo; andY represents OH, —O—SO₂—CF₃, Cl, Br, I, SH or —SO₂Cl.
 2. The methodaccording to claim 1, in which the compound of general formula (Ib) hasthe following formula:


3. A compound of general formula 5

in which R³ and R⁴ are as defined in claim
 1. 4. A compound of generalformula 4

in which R³ and R⁴ are as defined in claim
 1. 5. A process for preparinga compound of general formula 5 as defined in claim 3, said methodcomprising

reacting a compound of general formula 4 in an organic solvent with astrong base at a temperature between −20° C. and the organic solvent'sboiling point, preferably between −5° C. and 30° C., to obtain thecompound of general formula
 5. 6. The process according to claim 5, inwhich the strong base is lithium bis(trimethylsilyl)amide (LiHMDS),potassium bis(trimethylsilyl)amide (KHMDS), sodiumbis(trimethylsilyl)amide (NaHMDS) or lithium diisopropylamide (LDA). 7.The process according to claim 5, in which the organic solvent is anaprotic organic solvent.
 8. The process according to claim 7, in whichthe organic solvent is tetrahydrofuran or N,N-dimethylformamide.
 9. Acompound of general formula 11

in which R¹, R³ and R⁴ are as defined in claim
 1. 10. A compound ofgeneral formula 12

in which R¹, R³ and R⁴ are as defined in claim 1 and X representschloro, bromo or iodo.
 11. A compound of general formula 39

in which Y represents OH, —O—SO₂—CF₃, Cl, Br, I, SH or —SO₂Cl.
 12. Acompound of general formula 9

in which R³ and R⁴ are as defined in claim
 1. 13. A compound of generalformula 15

in which R¹, R³ and R⁴ are as defined in claim
 1. 14. A compound ofgeneral formula 16

in which R¹, R³ and R⁴ are as defined in claim
 1. 15. A compound ofgeneral formula 8

in which R¹ represents a group selected from:

wherein * indicates the point of attachment of said group with the restof the molecule; R³ and R⁴ represent, independently from each other,hydrogen or methyl.
 16. A method for preparing a compound of generalformula 8 as defined in claim 15, said method comprising

reacting a compound of general formula 7 in an organic solvent with astrong base at a temperature between −20° C. and the organic solvent'sboiling point to obtain the compound of general formula 8.